Note: Descriptions are shown in the official language in which they were submitted.
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COMBINATION OF AN ALLOSTERIC CARBOXYLIC INHIBITOR OF
MATRIX METALLOPROTEINASE-13 WITH CELECOXIB OR
VALDECOXIB
FIELD OF THE INVENTION
This invention provides a combination of an allosteric carboxylic inhibitor
of matrix metalloproteinase-13 with celecoxib or valdecoxib, a pharmaceutical
composition comprising the combination, and methods of using the combination
to treat diseases characterized by connective tissue breakdown, including
cartilage
damage, and inflammation or pain. Such diseases include arthritis, heart
failure,
multiple sclerosis, atherosclerosis, and osteoporosis.
BACKGROUND OF THE INVENTION
More than 23 million Americans have some form of arthritis. Among the
various forms of arthritis, osteoarthritis ("OA") is the most prevalent,
affecting 21
million Americans. Characterized by the degeneration of joint cartilage and
adjacent bone, OA is a chronic disorder that can cause pain and stiffness.
Rheumatoid arthritis ("RA"), which affects more than 2.1 million Americans, is
an autoimmune disease that affects joint lining, cartilage and bones.
Aspirin and conventional nonsteroidal anti-inflammatory drugs (NSAIDs)
such as ibuprofen, diclofenac, and naproxen are the primary agents used to
treat
OA- and RA-related pain. These agents inhibit prostaglandin release by
blocking
cyclooxygenase-mediated conversion of cell membrane lipids from arachidonic
acid.
Two forms of COX are now known, a constitutive isoform usually named
cyclooxygenase-1 ("COX-1") and an inducible isoform usually named
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cyclooxygenase-2 ("COX-2"), the latter of which expression is upregulated at
sites of inflammation. COX-1 appears to play a physiological role and to be
responsible for gastrointestinal and renal protection. On the other hand, COX-
2
appears to play a pathological role and is believed to be the predominant
isoform
present in inflammation conditions. The therapeutic use of conventional COX
inhibitors, which are typically nonselective inhibitors of both COX-1 and COX-
2,
is limited due to drug associated side effects, including life threatening
ulceration
and renal toxicity. Compounds that selectively inhibit COX-2 would exert anti-
inflammatory effects without the adverse side effects associated with COX-1
inhibition.
Valdecoxib is a COX-2 specific inhibitor that was approved in 2001 by the
United States Food and Drug Administration ("FDA") for treating the signs and
symptoms of osteoarthritis (OA) and adult rheumatoid arthritis (RA); and the
treatment of pain associated with menstrual cramping. Valdecoxib tablets are
marketed under the tradename BEXTRA~. In a combined analysis of various
clinical studies with valdecoxib, valdecoxib was well tolerated with an
overall
upper gastrointestinal safety profile (ulcers, perforations, obstructions and
GI
bleeds) significantly better than the conventional NSAIDs studied such as
ibuprofen, diclofenac and naproxen.
Matrix metalloproteinases ("MMPs") are naturally occurring enzymes
found in most mammals. Stromelysin-1 and gelatinase A are members of the
matrix metalloproteinases (MMP) family. Other members include fibroblast
collagenase (MMP-1), neutrophil collagenase (MMP-8), gelatinase B (92 kDa
gelatinase) (MMP-9), stromelysin-2 (MMP-10), stromelysin-3 (MMP-11),
matrilysin (MMP-7), collagenase 3 (MMP-13), and other newly discovered
membrane-associated matrix metalloproteinases.
Over-expression or activation of MMPs, or an imbalance between MMPs
and their endogenous inhibitors, namely tissue inhibitors of
metalloproteinases
("TIMPs"), have been suggested as factors in the pathogenesis of diseases
characterized by the breakdown of extracellular matrix or connective tissues.
These diseases include rheumatoid arthritis, osteoarthritis, osteoporosis,
periodontitis, multiple sclerosis, gingivitis, corneal epidermal and gastric
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ulceration, atherosclerosis, neointimal proliferation which leads to
restenosis and
ischemic heart failure, and tumor metastasis.
A major limitation on the use of currently known MMP inhibitors is their
lack of specificity for any particular MMP enzyme. Recent data has established
that specific MMP enzymes are associated with some diseases, with no effect on
others. The MMPs are generally categorized based on their substrate
specificity,
and indeed the collagenase subfamily of MMP-l, MMP-8, and MMP-13
selectively cleave native interstitial collagens, and thus are associated only
with
diseases linked to such interstitial collagen tissue. This is evidenced by the
recent
discovery that MMP-13 alone is over expressed in breast carcinoma, while
MMP-1 alone is over expressed in papillary carcinoma (see Chen et al., J. Am.
Chem. Soc., 2000;122:9648-9654).
Another major limitation of currently known MMP inhibitors related to
their lack of specificity for any particular MMP enzyme is their production of
undesirable side effects related to inhibition of multiple MMP enzymes and/or
tumor necrosis factor-alpha converting enzyme ("TACE"). One example of such a
side effect is musculoskeletal syndrome ("MSS").
There appears to be few selective inhibitors of MMP-13 reported. A
compound named WAY-170523 has been reported by Chen et al., supra., 2000,
and a few other compounds are reported in PCT International Patent Application
Publication Number WO 01/63244 A1, as allegedly selective inhibitors of
MMP-13. Further, United States Patent Number 6,008,243 discloses inhibitors of
MMP-13. These inhibitors contain functional groups that ligate, coordinate, or
bind the catalytic zinc cation on MMP-13. However, selectivity in these cases
can
mean only a 5-fold or 10-fold greater inhibition of MMP-13 versus as few as
one
other MMP enzyme. Further, no selective or non-allosteric carboxylic inhibitor
of
MMP-13 has been marketed for the treatment of any disease in any mammal.
Applicant has previously discovered highly selective inhibitors of MMP-
13 that show promising pharmacological and pharmacokinetic activity in vivo.
These inhibitors have been the subjects of previously filed patent
applications.
Applicant's inhibitors are more selective than prior art inhibitors for
MMP-13 versus other MMP enzymes, both in terms of relative potencies and in
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terms of the numbers of the other MMP enzymes. For example, some of
Applicant's inhibitors have shown 100-fold or greater selectivity with MMP-13
versus five or more other MMP enzymes, and further have shown efficacy in
animal models of osteoarthritis.
The observed selectivity of Applicant's inhibitors may be attributed to the
inhibitors' binding to MMP-13 at an allosteric site and, further, to a binding
mode
which does not involve binding to the enzyme's catalytic zinc. Prior to
Applicant's allosteric MMP-13 inhibitors, it is believed that all prior art
MMP-13
inhibitors bound to an MMP enzyme's catalytic zinc and occupied the MMP
enzyme's substrate binding site. This latter binding mode was erroneously
believed by others to be necessary for MMP-13 inhibitor potency.
Applicant's discovery that a combination of an allosteric carboxylic
inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof, with
celecoxib, or a pharmaceutically acceptable salt thereof, or valdecoxib, or a
pharmaceutically acceptable salt thereof, is particularly useful for treating
diseases
characterized by damage to connective tissue such as cartilage damage. All
that is
required to treat diseases characterized by damage to connective tissue such
as
cartilage damage, including osteoarthritis, heart failure, multiple sclerosis,
atherosclerosis, or osteoporosis in a mammal according to the invention is to
administer to the mammal in need of treatment a therapeutically effective
amount
of the combination, wherein the combination comprises an allosteric carboxylic
inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof, with
celecoxib, or a pharmaceutically acceptable salt thereof, or valdecoxib, or a
pharmaceutically acceptable salt thereof. As will be discussed below, the
instant
combination of an allosteric carboxylic inhibitor of MMP-13, or a
pharmaceutically acceptable salt thereof, with celecoxib, or a
pharmaceutically
acceptable salt thereof, or valdecoxib, or a pharmaceutically acceptable salt
thereof, possesses many advantages over any combination of a prior art
selective
inhibitor of MMP-13 with a COX-2 inhibitor.
SUMMARY OF THE INVENTION
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This invention provides a combination, comprising an allosteric carboxylic
inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof, with
celecoxib, or a pharmaceutically acceptable salt thereof, or valdecoxib, or a
pharmaceutically acceptable salt thereof.
Another invention embodiment is a combination, comprising celecoxib, or
a pharmaceutically acceptable salt thereof, and an allosteric carboxylic
inhibitor of
MMP-13, or a pharmaceutically acceptable salt thereof.
Other invention embodiments are described below:
1. A combination, comprising valdecoxib, or a pharmaceutically acceptable
salt thereof, and an allosteric carboxylic inhibitor of MMP-13 of Formula I
R1
R2
Y ~ X
I
R4iN N ~ R3
Y
or a pharmaceutically acceptable salt thereof,
wherein:
"---" is absent or is a bond;
X is O, S, SO, 502, CH2, C = O, CHOH, NH, or NRS;
YisOorS;
R1 is H, (O)nC 1-C6 alkyl, (O)n substituted C 1-C6 alkyl, N02, NRSR6, CHO, or
halo;
R2, R3, and R4 independently are hydrogen, halo, C1-C6 alkyl, substituted
C1-C6 alkyl, C2-C6 alkenyl, substituted C2-C6 alkenyl, C2-Clp alkynyl,
substituted C2-C10 alkynyl, (CH2)m OH, (CH2)m ORS, (CH2)m
cycloalkyl, (CH2)m substituted cycloalkyl, CHOH (CH2)m aryl, CHOH
(CH2)m substituted aryl, CHOH (CH2)m heteroaryl, CHOH (CH2)m
substituted heteroaryl, (C02)n(CH2)m aryl (C02)n(CH2)m substituted
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aryl, (C02)n(CH2)m heteroaryl, (C02)n(CH2)m substituted heteroaryl,
(C02)n(CH2)m carbocycle, (C02)n(CH2)m substituted carbocycle,
(C02)n(CH2)m heterocycle, (C02)n(CH2)m substituted heterocycle,
(CO2)n(CH2)m NRSR6, CH(CI-6 alkyl)-aryl, (CH2)m N(H) C(=O)aryl,
(CH2)m-S(O)0_2-(CH2)n-aryl, CH(CI-C6 alkyl)-substituted aryl,
(CH2)mN(H) C(=O) substituted aryl, (CH2)m-S(O)0_2-(CH2)n substituted
aryl,
C(=O)N(RS)-(CH2)m aryl, C(=O)N(RS)-(CH2)m substituted aryl,
C(=O)N(RS)-(CH2)m heteroaryl, C(=O)N(RS)-(CH2)m substituted
l0 heteroaryl, C=C-(CH2)m aryl, C=C-(CH2)m substituted aryl,
C=C-(CH2)m-heteroaryl, C=C-(CH2)m substituted heteroaryl,
C=C-(CH2)m carbocycle, C=C-(CH2)m substituted carbocycle,
(CH2)m-O-aryl, (CH2)m-O-substituted aryl, (CH2)m CORS
NH
(CH2)m CONRSR6, (CH2)m CNRSR6,
(CH2)m CNRSR6,
or (CH2)m C02R5;
m is an integer from 0 to 6;
RS and R6 independently are hydrogen, CI-C6 alkyl, substituted C1-C6 alkyl,
(CH2)m aryl, (CH2)m substituted aryl, (CH2)m heteroaryl or (CH2)m
substituted heteroaryl, or RS and R6 are taken together with the nitrogen
atom to which they are attached complete a 3- to 7-membered ring;
containing carbon atoms, the nitrogen atom bearing RS and R6, and
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optionally 1 or 2 heteroatoms independently selected form O, S, and NR2,
wherein R2 is as defined above and;
n is 0 or 1; with the proviso that R2 and R4 are not both selected from
hydrogen
and Cl-Cg alkyl.
2. The combination according to Embodiment l, wherein the compound of
Formula I is a compound of Formula III
R1
R2
O ~ S
III
R4~N~N R3
~[O
or a pharmaceutically acceptable salt thereof, wherein Rl, R2, R3, and R4 are
as
defined above for Embodiment 1.
3. The combination according to Embodiment 2, wherein the compound of
Formula III is selected from:
I S 6-Benzyl-8-methyl-5,7-dioxo-6,7-dihydro-SH-thiazolo[3,2-c]pyrimidine-
2-carbothioic acid benzylamide;
6-Benzyl-8-methyl-5,7-dioxo-6,7-dihydro-SH-thiazolo[3,2-c]pyrimidine-
2-carbothioic acid 4-methoxy-benzylamide;
6-Benzyl-2-(3-phenyl-propionyl)-thiazolo[3,2-c]pyrimidine-5,7-dione;
6-Benzyl-8-methyl-5,7-dioxo-6,7-dihydro-SH-thiazolo[3,2-c]pyrimidine-
2-carboxylic acid prop-2-ynylamide;
6-Benzyl-8-methyl-5,7-dioxo-6,7-dihydro-SH-thiazolo[3,2-c]pyrimidine-
2-carboxylic acid (piperidin-4-ylmethyl)-amide hydrochloride;
6-Benzyl-2-( 1-hydroxy-3-phenyl-al l yl)-8-methyl-
thiazolo[3,2-c]pyrimidine-5,7-dione;
6-Benzyl-2-( 1-hydroxy-3-phenyl-prop-2-ynyl)-8-methyl-
thiazolo[3,2-c]pyrimidine-5,7-dione;
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6-Benzyl-2-(hydroxy-phenyl-methyl)-thiazolo[3,2-c]pyrimidine-5,7-dione;
and
6-Benzyl-2-( 1-hydroxy-3-phenyl-propyl)-thiazolo[3,2-c]pyrimidine-
5,7-dione, or a pharmaceutically acceptable salt thereof.
4. The combination according to Embodiment 2, wherein the compound of
Formula III is selected from:
6-Benzyl-8-methyl-5,7-dioxo-6,7-dihydro-SH-thiazolo[3,2-c]pyrimidine-
2-carboxylic acid prop-2-ynylamide;
6-Benzyl-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo[3,2-c]pyrimidine-
2-carboxylic acid (piperidin-4-ylmethyl)-amide hydrochloride;
6-(4-Bromo-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-thiazolo[3,2-
c]pyrimidine-2-carboxylic acid (2-amino-pyridin-4-ylmethyl)-amide;
6-(4-Chloro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-thiazolo[3,2-
c]pyrimidine-2-carboxylic acid (2-amino-pyridin-4-ylmethyl)-amide;
6-(4-Fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-thiazolo[3,2-
c]pyrimidine-2-carboxylic acid (2-amino-pyridin-4-ylmethyl)-amide;
6-(3-Bromo-4-fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-
thiazolo[3,2-c]pyrimidine-2-carboxylic acid (2-amino-pyridin-4-ylmethyl)-
amide;
6-(3-Bromo-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-thiazolo[3,2-
c]pyrimidine-2-carboxylic acid (2-amino-pyridin-4-ylmethyl)-amide;
6-(3,4-Dichloro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo[3,2-
c]pyrimidine-2-carboxylic acid (2-amino-pyridin-4-ylmethyl)-amide;
6-(4-Bromo-3-fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-
. thiazolo[3,2-c]pyrimidine-2-carboxylic acid (2-amino-pyridin-4-ylmethyl)-
amide;
6-(3-Chloro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-thiazolo[3,2-
c]pyrimidine-2-carboxylic acid (2-amino-pyridin-4-ylmethyl)-amide;
6-(3-Fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-thiazolo[3,2-
c]pyrimidine-2-carboxylic acid (2-amino-pyridin-4-ylmethyl)-amide;
6-(3,4-Dibromo-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-thiazolo[3,2-
c]pyrimidine-2-carboxylic acid (2-amino-pyridin-4-ylmethyl)-amide;
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6-(4-Bromo-3-chloro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-
thiazolo[3,2-c]pyrimidine-2-carboxylic acid (2-amino-pyridin-4-ylmethyl)-
amide;
6-(3,4-Difluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo[3,2-
c]pyrimidine-2-carboxylic acid (2-amino-pyridin-4-ylmethyl)-amide;
' 6-(3-Bromo-4-chloro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-
thiazolo[3,2-c]pyrimidine-2-carboxylic acid (2-amino-pyridin-4-ylmethyl)-
amide;
6-(3-Chloro-4-fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-
thiazolo[3,2-c]pyrimidine-2-carboxylic acid (2-amino-pyridin-4-ylmethyl)-
amide;
6-(4-Chloro-3-fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-
thiazolo[3,2-c]pyrimidine-2-carboxylic acid (2-amino-pyridin-4-ylmethyl)-
amide;
6-(4-Bromo-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-thiazolo[3,2-
c]pyrimidine-2-carboxylic acid (2-ethoxy-pyridin-4-ylmethyl)-amide;
6-(4-Chloro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-thiazolo[3,2-
c]pyrimidine-2-carboxylic acid (2-ethoxy-pyridin-4-ylmethyl)-amide;
6-(4-Fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-thiazolo[3,2-
cJpyrimidine-2-carboxylic acid (2-ethoxy-pyridin-4-ylmethyl)-amide;
6-(3-Bromo-4-fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-
thiazolo[3,2-c]pyrimidine-2-carboxylic acid (2-ethoxy-pyridin-4-ylmethyl)-
amide;
6-(3-Bromo-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-thiazolo[3,2-
c]pyrimidine-2-carboxylic acid (2-ethoxy-pyridin-4-ylmethyl)-amide;
6-(3,4-Dichloro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-thiazolo[3,2-
c]pyrimidine-2-carboxylic acid (2-ethoxy-pyridin-4-ylmethyl)-amide;
6-(4-Bromo-3-fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-
thiazolo[3,2-c]pyrimidine-2-carboxylic acid (2-ethoxy-pyridin-4-ylmethyl)-
amide;
6-(3-Chloro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-thiazolo[3,2-
c]pyrimidine-2-carboxylic acid (2-ethoxy-pyridin-4-ylmethyl)-amide;
6-(3-Fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-thiazolo[3,2-
cJpyrimidine-2-carboxylic acid (2-ethoxy-pyridin-4-ylmethyl)-amide;
6-(3,4-Dibromo-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-thiazolo[3,2-
c]pyrimidine-2-carboxylic acid (2-ethoxy-pyridin-4-ylmethyl)-amide;
6-(4-Bromo-3-chloro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-
thiazolo[3,2-cJpyrimidine-2-carboxylic acid (2-ethoxy-pyridin-4-ylmethyl)-
amide;
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6-(3,4-Difluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-thiazolo[3,2-
c]pyrimidine-2-carboxylic acid (2-ethoxy-pyridin-4-ylmethyl)-amide;
6-(3-Bromo-4-chloro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-
thiazolo[3,2-c]pyrimidine-2-carboxylic acid (2-ethoxy-pyridin-4-ylmethyl)-
amide;
6-(3-Chloro-4-fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-
thiazolo[3,2-c]pyrimidine-2-carboxylic acid (2-ethoxy-pyridin-4-ylmethyl)-
amide;
6-(4-Chloro-3-fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-
thiazolo[3,2-c]pyrimidine-2-carboxylic acid (2-ethoxy-pyridin-4-ylmethyl)-
amide;
6-(4-Bromo-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-thiazolo[3,2-
l0 c]pyrimidine-2-carboxylic acid (6-hydroxy-pyridin-3-ylmethyl)-amide;
6-(4-Chloro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-thiazolo[3,2-
c]pyrimidine-2-carboxylic acid (6-hydroxy-pyridin-3-ylmethyl)-amide;
6-(4-Fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-thiazolo[3,2-
c]pyrimidine-2-carboxylic acid (6-hydroxy-pyridin-3-ylmethyl)-amide;
6-(3-Bromo-4-fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-
thiazolo[3,2-c]pyrimidine-2-carboxylic acid (6-hydroxy-pyridin-3-ylmethyl)-
amide;
6-(3-Bromo-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-thiazolo[3,2-
c]pyrimidine-2-carboxylic acid (6-hydroxy-pyridin-3-ylmethyl)-amide;
6-(3,4-Dichloro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-thiazolo[3,2-
c]pyrimidine-2-carboxylic acid (6-hydroxy-pyridin-3-ylmethyl)-amide;
6-(4-Bromo-3-fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-
thiazolo[3,2-c]pyrimidine-2-carboxylic acid (6-hydroxy-pyridin-3-ylmethyl)-
amide;
6-(3-Chloro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-thiazolo[3,2
c]pyrimidine-2-carboxylic acid (6-hydroxy-pyridin-3-ylmethyl)-amide;
6-(3-Fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-thiazolo[3,2-
c]pyrimidine-2-carboxylic acid (6-hydroxy-pyridin-3-ylmethyl)-amide;
6-(3,4-Dibromo-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-thiazolo[3,2-
c]pyrimidine-2-carboxylic acid (6-hydroxy-pyridin-3-ylmethyl)-amide;
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6-(4-Bromo-3-chloro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-
thiazolo[3,2-c]pyrimidine-2-carboxylic acid (6-hydroxy-pyridin-3-ylmethyl)-
amide;
6-(3,4-Difluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-thiazolo[3,2-
c]pyrimidine-2-carboxylic acid (6-hydroxy-pyridin-3-ylmethyl)-amide;
6-(3-Bromo-4-chloro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-
thiazolo[3,2-c]pyrimidine-2-carboxylic acid (6-hydroxy-pyridin-3-ylmethyl)-
amide;
6-(3-Chloro-4-fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-
10_ thiazolo[3,2-c]pyrimidine-2-carboxylic acid (6-hydroxy-pyridin-3-ylmethyl)-
amide;
6-(4-Chloro-3-fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-
thiazolo[3,2-c]pyrimidine-2-carboxylic acid (6-hydroxy-pyridin-3-ylmethyl)-
amide;
6-(4-Bromo-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-thiazolo[3,2-
c]pyrimidine-2-carboxylic acid (2-mettioxy-pyridin-4-ylmethyl)-amide;
6-(4-Chloro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-thiazolo[3,2-
c]pyrimidine-2-carboxylic acid (2-methoxy-pyridin-4-ylmethyl)-amide;
6-(4-Fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-thiazolo[3,2-
c]pyrimidine-2-carboxylic acid (2-methoxy-pyridin-4-ylmethyl)-amide;
6-(3-Bromo-4-fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-
thiazolo[3,2-c]pyrimidine-2-carboxylic acid (2-methoxy-pyridin-4-ylmethyl)-
amide;
6-(3-Bromo-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-thiazolo[3,2-
c]pyrimidine-2-carboxylic acid (2-methoxy-pyridin-4-ylmethyl)-amide;
6-(3,4-Dichloro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-thiazolo[3,2-
c]pyrimidine-2-carboxylic acid (2-methoxy-pyridin-4-ylmethyl)-amide;
6-(4-Bromo-3-fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-
thiazolo[3,2-c]pyrimidine-2-carboxylic acid (2-methoxy-pyridin-4-ylmethyl)-
amide;
6-(3-Chloro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-thiazolo[3,2-
c]pyrimidine-2-carboxylic acid (2-methoxy-pyridin-4-ylmethyl)-amide;
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6-(3-Fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo[3,2-
c]pyrimidine-2-carboxylic acid (2-methoxy-pyridin-4-ylmethyl)-amide;
6-(3,4-Dibromo-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo[3,2-
c]pyrimidine-2-carboxylic acid (2-methoxy-pyridin-4-ylmethyl)-amide;
6-(4-Bromo-3-chloro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-
thiazolo[3,2-c]pyrimidine-2-carboxylic acid (2-methoxy-pyridin-4-ylmethyl)-
amide;
6-(3,4-Difluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo[3,2-
c]pyrimidine-2-carboxylic acid (2-methoxy-pyridin-4-ylmethyl)-amide;
6-(3-Bromo-4-chloro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-
thiazolo[3,2-c]pyrimidine-2-carboxylic acid (2-methoxy-pyridin-4-ylmethyl)-
amide;
6-(3-Chloro-4-fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-
thiazolo[3,2-c]pyrimidine-2-carboxylic acid (2-methoxy-pyridin-4-ylmethyl)-
amide;
6-(4-Chloro-3-f7uoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-
thiazolo[3,2-c]pyrimidine-2-carboxylic acid (2-methoxy-pyridin-4-ylmethyl)-
amide;
6-(4-Bromo-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo[3,2-
c]pyrimidine-2-carboxylic acid (2-methyl-pyridin-4-ylmethyl)-amide;
6-(4-Chloro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo[3,2-
c]pyrimidine-2-carboxylic acid (2-methyl-pyridin-4-ylmethyl)-amide;
6-(4-Fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo[3,2-
c]pyrimidine-2-carboxylic acid (2-methyl-pyridin-4-ylmethyl)-amide;
6-(3-Bromo-4-fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-
thiazolo[3,2-c]pyrimidine-2-carboxylic acid (2-methyl-pyridin-4-ylmethyl)-
amide;
6-(3-Bromo-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo[3,2-
c]pyrimidine-2-carboxylic acid (2-methyl-pyridin-4-ylmethyl)-amide;
6-(3,4-Dichloro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo[3,2-
c]pyrimidine-2-carboxylic acid (2-methyl-pyridin-4-ylmethyl)-amide;
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6-(4-Bromo-3-fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH
thiazolo[3,2-c]pyrimidine-2-carboxylic acid (2-methyl-pyridin-4-ylmethyl)
amide;
6-(3-Chloro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-thiazolo[3,2-
c]pyrimidine-2-carboxylic acid (2-methyl-pyridin-4-ylmethyl)-amide;
6-(3-Fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-thiazolo[3,2-
c]pyrimidine-2-carboxylic acid (2-methyl-pyridin-4-ylmethyl)-amide;
6-(3,4-Dibromo-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-thiazolo[3,2-
c]pyrimidine-2-carboxylic acid (2-methyl-pyridin-4-ylmethyl)-amide;
6-(4-Bromo-3-chloro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-
thiazolo[3,2-c]pyrimidine-2-carboxylic acid (2-methyl-pyridin-4-ylmethyl)-
amide;
6-(3,4-Difluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-thiazolo[3,2-
c]pyrimidine-2-carboxylic acid (2-methyl-pyridin-4-ylmethyl)-amide;
6-(3-Bromo-4-chloro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-
thiazolo[3,2-c]pyrimidine-2-carboxylic acid (2-methyl-pyridin-4-ylmethyl)-
amide;
6-(3-Chloro-4-fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-
thiazolo[3,2-c]pyrimidine-2-carboxylic acid (2-methyl-pyridin-4-ylmethyl)-
amide;
6-(4-Chloro-3-f7uoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH
thiazolo[3,2-c]pyrimidine-2-carboxylic acid (2-methyl-pyridin-4-ylmethyl)
amide;
6-(4-Bromo-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-thiazolo[3,2-
c]pyrimidine-2-carboxylic acid (2-methylamino-pyridin-4-ylmethyl)-amide;
6-(4-Chloro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-thiazolo[3,2-
c]pyrimidine-2-carboxylic acid (2-methylamino-pyridin-4-ylmethyl)-amide;
6-(4-Fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-thiazolo[3,2-
c]pyrimidine-2-carboxylic acid (2-methylamino-pyridin-4-ylmethyl)-amide;
6-(3-Bromo-4-fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-
thiazolo[3,2-c]pyrimidine-2-carboxylic acid (2-methylamino-pyridin-4-ylmethyl)-
amide;
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6-(3-Bromo-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-thiazolo[3,2-
c]pyrimidine-2-carboxylic acid (2-methylamino-pyridin-4-ylmethyl)-amide;
6-(3,4-Dichloro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-thiazolo[3,2-
c]pyrimidine-2-carboxylic acid (2-methyl amino-pyridin-4-ylmethyl)-amide;
6-(4-Bromo-3-fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-
thiazolo[3,2-c]pyrimidine-2-carboxylic acid (2-methylamino-pyridin-4-ylmethyl)-
amide;
6-(3-Chloro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-thiazolo[3,2-
c]pyrimidine-2-carboxylic acid (2-methyl amino-pyridin-4-ylmethyl)-amide;
6-(3-Fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-thiazolo[3,2-
c]pyrimidine-2-carboxylic acid (2-methylamino-pyridin-4-ylmethyl)-amide;
6-(3,4-Dibromo-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-thiazolo[3,2-
c]pyrimidine-2-carboxylic acid (2-methyl amino-pyridin-4-ylmethyl)-amide;
6-(4-Bromo-3-chloro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-
thiazolo[3,2-c]pyrimidine-2-carboxylic acid (2-methylamino-pyridin-4-ylmethyl)-
amide;
6-(3,4-Difluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-thiazolo[3,2-
c]pyrimidine-2-carboxylic acid (2-methylamino-pyridin-4-ylmethyl)-amide;
6-(3-Chloro-4-fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-
thiazolo[3,2-c]pyrimidine-2-carboxylic acid (2-methylamino-pyridin-4-ylmethyl)-
amide;
6-(4-Chloro-3-fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-
thiazolo[3,2-c]pyrimidine-2-carboxylic acid (2-methylamino-pyridin-4-ylmethyl)-
amide;
6-(4-Chloro-3-bromo-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-
thiazolo[3,2-c]pyrimidine-2-carboxylic acid (2-methylamino-pyridin-4-ylmethyl)-
amide;
6-(4-Bromo-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-thiazolo[3,2-
c]pyrimidine-2-carboxylic acid (pyridin-3-ylmethyl)-amide;
6-(4-Chloro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-thiazolo[3,2-
c]pyrimidine-2-carboxylic acid (pyridin-3-ylmethyl)-amide;
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6-(4-Fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo[3,2-
c]pyrimidine-2-carboxylic acid (pyridin-3-ylmethyl)-amide;
6-(3-Bromo-4-fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-
thiazolo[3,2-c]pyrimidine-2-carboxylic acid (pyridin-3-ylmethyl)-amide;
' 6-(3-Bromo-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-thiazolo[3,2-
c]pyrimidine-2-carboxylic acid (pyridin-3-ylmethyl)-amide;
6-(3,4-Dichloro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-thiazolo[3,2-
c]pyrimidine-2-carboxylic acid (pyridin-3-ylmethyl)-amide;
6-(4-Bromo-3-fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-
thiazolo[3,2-c]pyrimidine-2-carboxylic acid (pyridin-3-ylmethyl)-amide;
6-(3-Chloro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-thiazolo[3,2-
c)pyrimidine-2-carboxylic acid (pyridin-3-ylmethyl)-amide;
6-(3-Fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-thiazolo[3,2-
c]pyrimidine-2-carboxylic acid (pyridin-3-ylmethyl)-amide;
' 6-(3,4-Dibromo-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-thiazolo[3,2-
c]pyrimidine-2-carboxylic acid (pyridin-3-ylmethyl)-amide;
6-(4-Bromo-3-chloro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-
thiazolo[3,2-c]pyrimidine-2-carboxylic acid (pyridin-3-ylmethyl)-amide;
6-(3,4-Difluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-thiazolo[3,2-
c]pyrimidine-2-carboxylic acid (pyridin-3-ylmethyl)-amide;
6-(3-Bromo-4-chloro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-
thiazolo[3,2-c]pyrimidine-2-carboxylic acid (pyridin-3-ylmethyl)-amide;
6-(3-Chloro-4-fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-
thiazolo[3,2-c]pyrimidine-2-carboxylic acid (pyridin-3-ylmethyl)-amide;
6-(4-Chloro-3-fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-
thiazolo[3,2-c]pyrimidine-2-carboxylic acid (pyridin-3-ylmethyl)-amide;
6-(4-Bromo-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-thiazolo[3,2-
c]pyrimidine-2-carboxylic acid (6-amino-pyridin-3-ylmethyl)-amide;
6-(4-Chloro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-thiazolo[3,2-
c]pyrimidine-2-carboxylic acid (6-amino-pyridin-3-ylmethyl)-amide;
6-(4-Fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-thiazolo[3,2-
c]pyrimidine-2-carboxylic acid (6-amino-pyridin-3-ylmethyl)-amide;
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6-(3-Bromo-4-fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-
thiazolo[3,2-c]pyrimidine-2-carboxylic acid (6-amino-pyridin-3-ylmethyl)-
amide;
6-(3-Bromo-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-thiazolo[3,2-
c]pyrimidine-2-carboxylic acid (6-amino-pyridin-3-ylmethyl)-amide;
6-(3,4-Dichloro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-thiazolo(3,2-
c]pyrimidine-2-carboxylic acid (6-amino-pyridin-3-ylmethyl)-amide;
6-(4-Bromo-3-fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-
thiazolo[3,2-c]pyrimidine-2-carboxylic acid (6-amino-pyridin-3-ylmethyl)-
amide;
6-(3-Chloro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-thiazolo[3,2-
c]pyrimidine-2-carboxylic acid (6-amino-pyridin-3-ylmethyl)-amide;
6-(3-Fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-thiazolo[3,2-
c]pyrimidine-2-carboxylic acid (6-amino-pyridin-3-ylmethyl)-amide;
6-(3,4-Dibromo-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-thiazolo[3,2-
c]pyrimidine-2-carboxylic acid (6-amino-pyridin-3-ylmethyl)-amide;
6-(4-Bromo-3-chloro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-
thiazolo[3,2-c]pyrimidine-2-carboxylic acid (6-amino-pyridin-3-ylmethyl)-
amide;
6-(3,4-Difluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-thiazolo[3,2-
c]pyrimidine-2-carboxylic acid (6-amino-pyridin-3-ylmethyl)-amide;
6-(3-Bromo-4-chloro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-
thiazolo[3,2-c]pyrimidine-2-carboxylic acid (6-amino-pyridin-3-ylmethyl)-
amide;
6-(3-Chloro-4-fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-
thiazolo[3,2-c]pyrimidine-2-carboxylic acid (6-amino-pyridin-3-ylmethyl)-
amide;
6-(4-Chloro-3-fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-
thiazolo[3,2-c]pyrimidine-2-carboxylic acid (6-amino-pyridin-3-ylmethyl)-
amide;
6-(4-Bromo-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-thiazolo[3,2-
c]pyrimidine-2-carboxylic acid (6-ethoxy-pyridin-3-ylmethyl)-amide;
6-(4-Chloro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-thiazolo[3,2-
c]pyrimidine-2-carboxylic acid (6-ethoxy-pyridin-3-ylmethyl)-amide;
6-(4-Fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-thiazolo[3,2-
c]pyrimidine-2-carboxylic acid (6-ethoxy-pyridin-3-ylmethyl)-amide;
6-(3-Bromo-4-fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-
thiazolo[3,2-c]pyrimidine-2-carboxylic acid (6-ethoxy-pyridin-3-ylmethyl)-
amide;
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6-(3-Bromo-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-thiazolo[3,2-
c]pyrimidine-2-carboxylic acid (6-ethoxy-pyridin-3-ylmethyl)-amide;
6-(3,4-Dichloro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-thiazolo[3,2-
c]pyrimidine-2-carboxylic acid (6-ethoxy-pyridin-3-ylmethyl)-amide;
6-(4-Bromo-3-fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-
thiazolo[3,2-c]pyrimidine-2-carboxylic acid (6-ethoxy-pyridin-3-ylmethyl)-
amide;
6-(3-Chloro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-thiazolo[3,2-
c]pyrimidine-2-carboxylic acid (6-ethoxy-pyridin-3-ylmethyl)-amide;
6-(3-Fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-thiazolo[3,2-
c]pyrimidine-2-carboxylic acid (6-ethoxy-pyridin-3-ylmethyl)-amide;
6-(3,4-Dibromo-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-thiazolo[3,2-
c]pyrimidine-2-carboxylic acid (6-ethoxy-pyridin-3-ylmethyl)-amide;
6-(4-Bromo-3-chloro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-
thiazolo[3,2-c]pyrimidine-2-carboxylic acid (6-ethoxy-pyridin-3-ylmethyl)-
amide;
~ 6-(3,4-Difluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-thiazolo[3,2-
c]pyrimidine-2-carboxylic acid (6-ethoxy-pyridin-3-ylmethyl)-amide;
6-(3-Bromo-4-chloro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-
thiazolo[3,2-c]pyrimidine-2-carboxylic acid (6-ethoxy-pyridin-3-ylmethyl)-
amide;
6-(3-Chloro-4-fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-
thiazolo[3,2-c]pyrimidine-2-carboxylic acid (6-ethoxy-pyridin-3-ylmethyl)-
amide;
6-(4-Chloro-3-fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-
thiazolo[3,2-c]pyrimidine-2-carboxylic acid (6-ethoxy-pyridin-3-ylmethyl)-
amide;
6-(4-Bromo-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo[3,2-
c]pyrimidine-2-carboxylic acid (6-methoxy-pyridin-3-ylmethyl)-amide;
6-(4-Chloro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-thiazolo[3,2-
c]pyrimidine-2-carboxylic acid (6-methoxy-pyridin-3-ylmethyl)-amide;
6-(4-Fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-thiazolo[3,2-
c]pyrimidine-2-carboxylic acid (6-methoxy-pyridin-3-ylmethyl)-amide;
6-(3-Bromo-4-fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-
thiazolo[3,2-c]pyrimidine-2-carboxylic acid (6-methoxy-pyridin-3-ylmethyl)-
amide;
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6-(3-Bromo-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-thiazolo[3,2-
c]pyrimidine-2-carboxylic acid (6-methoxy-pyridin-3-ylmethyl)-amide;
6-(3,4-Dichloro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-thiazolo[3,2-
c]pyrimidine-2-carboxylic acid (6-methoxy-pyridin-3-ylmethyl)-amide;
6-(4-Bromo-3-fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-
thiazolo[3,2-c]pyrimidine-2-carboxylic acid (6-methoxy-pyridin-3-ylmethyl)-
amide;
6-(3-Chloro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-thiazolo[3,2-
c]pyrimidine-2-carboxylic acid (6-methoxy-pyridin-3-ylmethyl)-amide;
6-(3-Fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-thiazolo[3,2-
c]pyrimidine-2-carboxylic acid (6-methoxy-pyridin-3-ylmethyl)-amide;
6-(3,4-Dibromo-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-thiazolo[3,2-
c]pyrimidine-2-carboxylic acid (6-methoxy-pyridin-3-ylmethyl)-amide;
6-(4-Bromo-3-chloro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-
1 S thiazolo[3,2-c]pyrimidine-2-carboxylic acid (6-methoxy-pyridin-3-ylmethyl)-
amide;
6-(3,4-Difluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-thiazolo[3,2-
c]pyrimidine-2-carboxylic acid (6-methoxy-pyridin-3-ylmethyl)-amide;
6-(3-Bromo-4-chloro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-
thiazolo[3,2-c]pyrimidine-2-carboxylic acid (6-methoxy-pyridin-3-ylmethyl)-
amide;
6-(3-Chloro-4-fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-
thiazolo[3,2-c]pyrimidine-2-carboxylic acid (6-methoxy-pyridin-3-ylmethyl)-
amide;
6-(4-Chloro-3-fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-
thiazolo[3,2-c]pyrimidine-2-carboxylic acid (6-methoxy-pyridin-3-ylmethyl)-
amide;
6-(4-Bromo-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-thiazolo[3,2-
c]pyrimidine-2-carboxylic acid (6-methyl-pyridin-3-ylmethyl)-amide;
6-(4-Chloro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-thiazolo[3,2-
c]pyrimidine-2-carboxylic acid (6-methyl-pyridin-3-ylmethyl)-amide;
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6-(4-Fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-thiazolo[3,2-
c]pyrimidine-2-carboxylic acid (6-methyl-pyridin-3-ylmethyl)-amide;
6-(3-Bromo-4-fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-
thiazolo[3,2-c]pyrimidine-2-carboxylic acid (6-methyl-pyridin-3-ylmethyl)-
amide;
6-(3-Bromo-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-thiazolo[3,2-
c]pyrimidine-2-carboxylic acid (6-methyl-pyridin-3-ylmethyl)-amide;
6-(3,4-Dichloro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-thiazolo[3,2-
c]pyrimidine-2-carboxylic acid (6-methyl-pyridin-3-ylmethyl)-amide;
6-(4-Bromo-3-fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-
thiazolo[3,2-c]pyrimidine-2-carboxylic acid (6-methyl-pyridin-3-ylmethyl)-
amide;
6-(3-Chloro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-thiazolo[3,2-
c]pyrimidine-2-carboxylic acid (6-methyl-pyridin-3-ylmethyl)-amide;
6-(3-Fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-thiazolo[3,2-
c]pyrimidine-2-carboxylic acid (6-methyl-pyridin-3-ylmethyl)-amide;
6-(3,4-Dibromo-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-thiazolo[3,2-
c]pyrimidine-2-carboxylic acid (6-methyl-pyridin-3-ylmethyl)-amide;
6-(4-Bromo-3-chloro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-
thiazolo[3,2-c]pyrimidine-2-carboxylic acid (6-methyl-pyridin-3-ylmethyl)-
amide;
6-(3,4-Difluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-thiazolo[3,2-
c]pyrimidine-2-carboxylic acid (6-methyl-pyridin-3-ylmethyl)-amide;
6-(3-Bromo-4-chloro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-
thiazolo[3,2-c]pyrimidine-2-carboxylic acid (6-methyl-pyridin-3-ylmethyl)-
amide;
6-(3-Chloro-4-fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-
thiazolo[3,2-c]pyrimidine-2-carboxylic acid (6-methyl-pyridin-3-ylmethyl)-
amide;
6-(4-Chloro-3-fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-
thiazolo[3,2-c]pyrimidine-2-carboxylic acid (6-methyl-pyridin-3-ylmethyl)-
amide;
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6-(4-Cyano-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-thiazolo[3,2-
c]pyrimidine-2-carboxylic acid (2-methoxy-pyridin-4-ylmethyl)-amide; and
6-(4-Isopropylsulfamoyl-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-
thiazolo[3,2-c]pyrimidine-2-carboxylic acid (2-methoxy-pyridin-4-ylmethyl)-
amide, or a pharmaceutically acceptable salt thereof.
5. The combination according to Embodiment l, wherein the compound of
Formula I is a compound of Formula IV
R1
R2
O ~ O
IV
~N N
R4 ~ R3
O
or a pharmaceutically acceptable salt thereof, wherein Rl, R2, R3, and R4 are
as
defined above for Embodiment 1.
6. The combination according to Embodiment 5, wherein the compound of
Formula IV is selected from:
6-Benzyl-8-methyl-5,7-dioxo-6,7-dihydro-SH-oxazolo[3,2-c]pyrimidine-
2-carboxylic acid benzyl ester;
6-Benzyl-5,7-dioxo-6,7-dihydro-SH-oxazolo[3,2-c]pyrimidine-
2-carboxylic acid benzyl ester;
6-Benzyl-5,7-dioxo-6,7-dihydro-5H-oxazolo[3,2-c]pyrimidine-2-
carboxylic acid benzylamide;
6-Benzyl-8-methyl-5,7-dioxo-6,7-dihydro-SH-oxazolo[3,2-c]pyrimidine-
2-carboxylic acid 4-methoxy-benzylamide;
6-Benzyl-8-methyl-5,7-dioxo-6,7-dihydro-SH-oxazolo[3,2-c]pyrimidine-
2-carboxylic acid (pyridin-4-ylmethyl)-amide; and
6-Benzyl-8-methyl-5,7-dioxo-6,7-dihydro-SH-oxazolo[3,2-c]pyrimidine-
2-carboxylic acid (benzo[1,3]dioxol-5-ylmethyl)-amide, or a pharmaceutically
acceptable salt thereof.
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7. The combination according to Embodiment 1, wherein the compound of
Formula I is a compound of Formula V
Rl
R2
O
V
~N~N
R ~4
O
or a pharmaceutically acceptable salt thereof, wherein R1 is hydrogen, (O)n CI-
C6 alkyl, or (O)n substituted C1-C6 alkyl, R2 is C02(CH2)m aryl,
C02(CH2)m substituted aryl,
NH
R4 is (CH2)m C02R5, (CH2)m CONRSR6, (CH2)m CNRSR6, CHOH (CH2)m
aryl, CHOH (CH2)m substituted aryl, CHOH (CH2)m heteroaryl, CHOH (CH2)m
substituted aryl.
8. The combination according to Embodiment 1, wherein the compound of
Formula I is a compound of Formula VI:
Rl
R2
Y ~ X
VI
R4~N~N R3
~Y
or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, Y, and
X
are as defined above for Embodiment 1.
9. The combination according to Embodiment 8, wherein the compound of
Formula VI is selected from:
6-Benzyl-8-methyl-5,7-dioxo-1,5,6,7-tetrahydro-imidazo[1,2-
c]pyrimidine-2-carboxylic acid (benzo[1,3]dioxol-5-ylmethyl)-amide;
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6-Benzyl-1,8-dimethyl-5,7-dioxo-1,5,6,7-tetrahydro-imidazo[ 1,2-
c]pyrimidine-2-carboxylic acid (benzo[1,3]dioxol-5-ylmethyl)-amide;
6-Benzyl-I ,8-dimethyl-5,7-dioxo-1,5,6,7-tetrahydro-imidazo[ 1,2-
c]pyrimidine-2-carboxylic acid benzylamide;
6-Benzyl-1,8-dimethyl-5,7-dioxo-1,5,6,7-tetrahydro-imidazo[1,2-
c]pyrimidine-2-carboxylic acid 4-methoxy-benzylamide;
6-Benzyl-1-methyl-5,7-dioxo-1,5,6,7-tetrahydro-imidazo[ 1,2-
c]pyrimidine-2-carboxylic acid 4-methoxy-benzylamide;
6-(4-Methoxy-benzyl)-I -methyl-5,7-dioxo-1,5,6,7-tetrahydro-imidazo[ 1,2-
c]pyrimidine-2-carboxylic acid 4-methoxy-benzylamide;
6-(4-Methoxy-benzyl)-1,8-dimethyl-5,7-dioxo-1,5,6,7-tetrahydro-
imidazo[1,2-c]pyrimidine-2-carboxylic acid (pyridin-4-ylmethyl)-amide;
6-Benzyl-5,7-dioxo-2,3,6,7-tetrahydro-5H-thiazolo[3,2-c]pyrimidine-
2-carboxylic acid benzyl ester 2,3-Dihydroxypropionic acid benzyl ester;
6-Benzyl-5,7-dioxo-2,3,6,7-tetrahydro-5H-thiazolo[3,2-c]pyrimidine-
2-carboxylic acid pyridin-4-ylmethyl ester hydrochloride;
6-Benzyl-1,5,7-trioxo-I ,2,3,5,6,7-hexahydro-
ll4-thiazolo[3,2-c]pyrimidine-3-carboxylic acid benzyl ester;
6-Benzyl-1,8-dimethyl-5,7-dioxo-1,5,6,7-tetrahydro-imidazo-
[1,2-c]pyrimidine-2-carboxylic acid 4-methoxy-benzyl ester; and
6-benzyl-3-ethoxy-2,3-dihydro-oxazolo[3,2-c]pyrimidine-5,7-dione, or a
pharmaceutically acceptable salt thereof.
10. The combination according to Embodiment 1, wherein the compound of
Formula I is a compound of Formula VII
RI ( i )1-2
O ~ S , R2
VII
R4'N~N R3
~O
or a pharmaceutically acceptable salt thereof, wherein RI, R2, R3, and R4 are
as
defined above for Embodiment 1.
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ll. The combination according to Embodiment 1, wherein the compound of
Formula I is a compound of Formula VIII
' O
R2 VIII
R4
O R3
or a pharmaceutically acceptable salt thereof, wherein:
R1 is H, CH3, CH20H, or CHO;
R2 is (C02)(CH2)m aryl, (C02)(CH2)m substituted aryl, (C02)(CH2)m
heteroaryl, (C02)(CH2)m substituted heteroaryl,
C(=O)N(RS)-(CH2)m-aryl, C(=O)N(RS)-(CH2)m substituted aryl,
C(=O)N(RS)-(CH2)m heteroaryl, C(=O)N(RS)-(CH2)m substituted
heteroaryl, C=C-(CH2)maryl, C=C-(CH2)m substituted aryl,
C=C-(CH2)m heteroaryl, or C=C-(CH2)m substituted heteroaryl, wherein
RS is hydrogen or methyl;
R3 is hydrogen or fluoro;
R4 is C2-C6 alkenyl, substituted C2-C6 alkenyl, C1-C6 alkyl, substituted C1-C6
alkyl, C2-C10 alkenyl, substituted C2-Cl0 alkynyl, (CH2)mCORS,
(CH2)mS(O)0_2-(CH2)naryl, C(=O)N(RS)-CH2)marYl, (CH2)m-O-arYl~
(CH2)mS(O)0-2-(CH2)n substituted aryl, C(=O)N(RS)-CH2)m substituted
aryl, (CH2)m-O-substituted aryl, (C02)n(CH2)m aryl, (C02)n(CH2)m
substituted aryl, (C02)n(CH2)m heteroaryl, (C02)n(CH2)m substituted
heteroaryl, (C02)n(CH2)m carbocycle, or (C02)n(CH2)m substituted
carbocycle, wherein
R1
S
~N N
nis0orl;
m is an integer of from 0 to 6; and
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RS is as defined above for Embodiment 1.
12. The combination according to Embodiment 1 l, wherein the compound of
Formula VIII is a compound selected from:
4-[8-Methyl-5,7-dioxo-2-(3-phenyl-prop-1-ynyl)-7H-thiazolo(3,2-
c]pyrimidin-6-ylmethyl]-benzoic acid;
4-{ 2-[3-(4-Methoxy-phenyl)-prop-1-ynyl]-8-methyl-5,7-dioxo-7H-
thiazolo[3,2-c]pyrimidin-6-ylmethyl }-benzoic acid;
4-{ 2-[3-(4-Fluoro-phenyl)-prop-1-ynyl]-8-methyl-5,7-dioxo-7H-
thiazolo[3,2-c]pyrimidin-6-ylmethyl }-benzoic acid;
4-{ 2-[3-(3-Methoxy-phenyl)-prop-1-ynyl]-8-methyl-5,7-dioxo-7H-
thiazolo[3,2-c]pyrimidin-6-ylmethyl }-benzoic acid;
4-{2-[3-(3,4-Difluoro-phenyl)-prop-1-ynyl]-8-methyl-5,7-dioxo-7H-
thiazolo[3,2-c]pyrimidin-6-ylmethyl}-benzoic acid;
6-Benzyl-8-methyl-2-(3-pyridin-4-yl-prop-1-ynyl)-thiazolo[3,2-
c]pyrimidine-5,7-dione;
6-(3,4-Dichloro-benzyl)-8-methyl-2-(3-pyridin-4-yl-prop-1-ynyl)-
thiazolo[3,2-c]pyrimidine-5,7-dione;
6-(3,4-Dichloro-benzyl)-2-[3-(2-methoxy-pyridin-4-yl)-prop-1-ynyl]-8-
methyl-thiazolo[3,2-c]pyrimidine-5,7-dione;
6-Benzyl-8-methyl-2-phenylethynyl-thiazolo[3,2-c]pyrimidine-5,7-dione;
6-(4-Bromo-benzyl)-2-[3-(3-methoxy-phenyl)-prop-1-ynyl]-8-methyl-
thiazolo[3,2-c]pyrimidine-5,7-dione;
4-{ 2-[3-(3-Methoxy-phenyl)-prop-1-ynyl]-8-methyl-5,7-dioxo-7H-
thiazolo[3,2-c]pyrimidin-6-ylmethyl }-benzenesulfonamide;
4-{ 2-[3-(3-Fluoro-4-methoxy-phenyl)-prop-1-ynyl]-8-methyl-5,7-dioxo-
7H-thiazolo[3,2-c]pyrimidin-6-ylmethyl }-benzoic acid;
6-(4-Fluoro-benzyl)-8-methyl-2-(3-phenyl-prop-1-ynyl)-thiazolo[3,2-
c]pyrimidine-5,7-dione;
6-Benzyl-8-methyl-2-(3-phenyl-prop-1-ynyl)-thiazolo[3,2-c]pyrimidine-
5,7-dione;
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6-(3,4-Dichloro-benzyl)-2-[3-(3-methoxy-phenyl)-prop-1-ynyl]-8-methyl-
thiazolo[3,2-c]pyrimidine-5,7-dione;
6-(4-Methanesulfonyl-benzyl)-8-methyl-2-(3-pyridin-4-yl-prop-1-ynyl)-
thiazolo[3,2-c]pyrimidine-5,7-dione;
' 4-{2-[3-(3-Methoxy-phenyl)-prop-1-ynyl]-8-methyl-5,7-dioxo-7H-
thiazolo[3,2-c]pyrimidin-6-ylmethyl }-benzonitrile;
4-[8-Methyl-5,7-dioxo-2-(3-phenyl-prop-1-ynyl)-7H-thiazolo[3,2-
c]pyrimidin-6-ylmethyl]-benzoic acid;
2-[3-(3-Methoxy-phenyl)-prop-1-ynyl]-8-methyl-6-[4-(2H-tetrazol-5-yl)-
benzyl]-thiazolo[3,2-c]pyrimidine-5,7-dione;
6-Benzyl-2-[3-(3-methoxy-phenyl)-prop-1-ynyl]-8-methyl-thiazolo[3,2-
c]pyrimidine-5,7-dione;
6-Benzyl-8-methyl-2-(3-phenyl-prop-1-ynyl)-thiazolo[3,2-c]pyrimidine-
5,7-dione;
2-[3-(3-Methoxy-phenyl)-prop-1-ynyl]-8-methyl-6-[4-(morpholine-4-
carbonyl)-benzyl]-thiazolo[3,2-c]pyrimidine-5,7-dione;
8-Methyl-6-[4-(morpholine-4-sulfonyl)-benzyl]-2-(3-pyridin-4-yl-prop-1-
ynyl)-thiazolo[3,2-c]pyrimidine-5,7-dione;
2-[3-(4-Fl uoro-phen yl )-prop-1-ynyl ]-8-methyl-6-(2-oxo-2H-1-
benzopyran-6-ylmethyl)-thiazolo[3,2-c]pyrimidine-5,7-dione;
2-[3-(3-Methoxy-phenyl)-prop-1-ynyl]-8-methyl-6-(2-oxo-2H-1-
benzopyran-6-ylmethyl)-thiazolo[3,2-c]pyrimidine-5,7-dione;
4-[8-Methyl-5,7-dioxo-2-(4-phenyl-but-l -ynyl)-7H-thiazolo[3,2-
c]pyrimidin-6-ylmethyl]-benzoic acid;
4-[8-Methyl-5,7-dioxo-2-(6-phenyl-hex-1-ynyl)-7H-thiazolo[3,2-
c]pyrimidin-6-ylmethyl]-benzoic acid;
4-[8-Methyl-5,7-dioxo-2-(5-phenyl-pent-l -ynyl)-7H-thiazolo[3,2-
c]pyrimidin-6-ylmethyl]-benzoic acid;
4-[8-Methyl-5,7-dioxo-2-(7-phenyl-kept-1-ynyl)-7H-thiazolo[3,2-
c]pyrimidin-6-ylmethyl]-benzoic acid;
(4-{ 2-[3-(3,4-Difluoro-phenyl)-prop-1-ynyl]-8-methyl-5,7-dioxo-7H-
thiazolo[3,2-c]pyrimidin-6-ylmethyl }-phenyl)-acetic acid;
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6-(3-Fluoro-benzyl)-8-methyl-2-(3-pyridin-4-yl-prop-1-ynyl)-thiazolo[3,2-
c]pyrimidine-5,7-dione;
6-(3,4-Difluoro-benzyl)-.8-methyl-2-(3-pyridin-4-yl-prop-1-ynyl)-
thiazolo[3,2-c]pyrimidine-5,7-dione;
6-(3-Fluoro-benzyl)-2-[3-(2-methoxy-pyridin-4-yl)-prop-1-ynyl]-8-
methyl-thiazolo[3,2-c]pyrimidine-5,7-dione;
[3-(8-Methyl-5,7-dioxo-2-phenylethynyl-7H-thiazolo[3,2-c]pyrimidin-6-
ylmethyl)-phenyl]-acetic acid;
6-(4-Bromo-benzyl)-2-[3-(4-fluoro-3-methoxy-phenyl)-prop-1-ynyl]-8-
methyl-thiazolo[3,2-c]pyrimidine-5,7-dione;
4-{ 2-[3-(3-Methoxy-phenyl)-prop-1-ynyl]-8-methyl-5,7-dioxo-7H-
thiazolo[3,2-c]pyrimidin-6-ylmethyl }-N,N-dimethyl-benzenesulfonamide;
4-{ 2-[3-(3-Fluoro-4-methoxy-phenyl)-prop-1-ynyl]-8-methyl-5,7-dioxo-
7H-thiazolo[3,2-c]pyrimidin-6-ylmethyl}-cyclohexanecarboxylic acid;
6-(3,4-Difluoro-benzyl)-2-[3-(3,4-difluoro-phenyl)-prop-l -ynyl]-8-methyl-
thiazolo[3,2-c]pyrimidine-5,7-dione;
4-[8-Methyl-5,7-dioxo-2-(3-phenyl-prop-1-ynyl)-7H-thiazolo[3,2-
c]pyrimidin-6-ylmethyl]-cyclohexanecarboxylic acid;
2-Chloro-4-{ 2-[3-(3-methoxy-phenyl)-prop-1-ynyl]-8-methyl-5,7-dioxo-
7H-thiazolo[3,2-c]pyrimidin-6-ylmethyl }-benzoic acid;
2-[3-(4-Fluoro-phenyl)-prop-1-ynyl]-6-(4-methanesulfonyl-benzyl)-8-
methyl-thiazolo[3,2-c]pyrimidine-5,7-dione;
4-{ 2-[3-(4-Fluoro-3-methoxy-phenyl)-prop-1-ynyl]-8-methyl-5,7-dioxo-
7H-thiazolo[3,2-c]pyrimidin-6-ylmethyl }-benzonitrile;
(3-{2-[3-(4-Fluoro-3-methoxy-phenyl)-prop-1-ynyl]-8-methyl-5,7-dioxo-
7H-thiazolo[3,2-c]pyrimidin-6-ylmethyl }-phenyl)-acetic acid;
(4-{ 2-[3-(3-Methoxy-phenyl)-prop-1-ynyl]-8-methyl-5,7-dioxo-7H-
thiazolo[3,2-c]pyrimidin-6-ylmethyl }-phenyl)-acetic acid;
6-(3,4-Difluoro-benzyl)-8-methyl-2-(3-phenyl-prop-1-ynyl)-thiazolo[3,2-
c]pyrimidine-5,7-dione;
2-[3-(3-Methoxy-phenyl)-prop-1-ynyl]-8-methyl-6-[4-(thiomorpholine-4-
carbonyl)-benzyl]-thiazolo[3,2-c]pyrimidine-5,7-dione;
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8-Methyl-2-(3-pyridin-4-yl-prop-l -ynyl)-6-[4-(thiomorpholine-4-
sulfonyl)-benzyl]-thiazolo[3,2-c]pyrimidine-5,7-dione;
2-[3-(4-Fluoro-3-methoxy-phenyl)-prop-1-ynyl]-8-methyl-6-(2-oxo-2H-1-
benzopyran-6-ylmethyl)-thiazolo[3,2-c]pyrimidine-5,7-dione; and
' 2-[3-(3-Methoxy-4-methyl-phenyl)-prop-l-ynyl]-8-methyl-6-(2-oxo-2H-1-
benzopyran-6-ylmethyl)-thiazolo[3,2-c]pyrimidine-5,7-dione, or a
pharmaceutically acceptable salt thereof.
13. The combination according to Embodiment l l, wherein the compound of
Formula VIII is a compound selected from:
4-[8-Methyl-5,7-dioxo-2-(3-phenyl-prop-l -ynyl)-7H-thiazolo[3,2-
c]pyrimidin-6-ylmethyl]-benzoic acid;
4-{ 2-[3-(4-Methoxy-phenyl)-prop-1-ynyl]-8-methyl-5,7-dioxo-7H-
thiazolo[3,2-c]pyrimidin-6-ylmethyl }-benzoic acid;
4-{2-[3-(4-Fluoro-phenyl)-prop-1-ynyl]-8-methyl-5,7-dioxo-7H-
thiazolo[3,2-c]pyrimidin-6-ylmethyl }-benzoic acid;
4-{ 2-[3-(3-Methoxy-phenyl)-prop-1-ynyl]-8-methyl-5,7-dioxo-7H-
thiazolo[3,2-c]pyrimidin-6-ylmethyl}-benzoic acid;
4-{ 2-[3-(3,4-Difluoro-phenyl)-prop-1-ynyl]-8-methyl-5,7-dioxo-7H-
thiazolo[3,2-c]pyrimidin-6-ylmethyl }-benzoic acid;
6-Benzyl-8-methyl-2-(3-pyridin-4-yl-prop-l -ynyl)-thiazolo[3,2-
c]pyrimidine-5,7-dione;
6-(3,4-Dichloro-benzyl)-8-methyl-2-(3-pyridin-4-yl-prop-1-ynyl)-
thiazolo[3,2-c]pyrimidine-5,7-dione;
6-(3,4-Dichloro-benzyl)-2-[3-(2-methoxy-pyridin-4-yl)-prop-1-ynyl]-8-
methyl-thiazolo[3,2-c]pyrimidine-5,7-dione;
6-Benzyl-8-methyl-2-phenylethynyl-thiazolo[3,2-c]pyrimidine-5,7-dione;
6-(4-Bromo-benzyl)-2-[3-(3-methoxy-phenyl)-prop-1-ynyl]-8-methyl-
thiazolo(3,2-c]pyrimidine-5,7-dione;
4-{2-[3-(3-Methoxy-phenyl)-prop-I-ynyl]-8-methyl-5,7-dioxo-7H-
thiazolo[3,2-c]pyrimidin-6-ylmethyl }-benzenesulfonamide;
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4-{ 2-[3-(3-Fluoro-4-methoxy-phenyl)-prop-l -ynyl]-8-methyl-5,7-dioxo-
7H-thiazolo[3,2-c]pyrimidin-6-ylmethyl }-benzoic acid;
6-(4-Fluoro-benzyl)-8-methyl-2-(3-phenyl-prop-1-ynyl)-thiazolo[3,2-
c]pyrimidine-5,7-dione;
6-Benzyl-8-methyl-2-(3-phenyl-prop-1-ynyl)-thiazolo[3,2-c]pyrimidine-
5,7-dione;
6-(3,4-Dichloro-benzyl)-2-[3-(3-methoxy-phenyl)-prop-1-ynyl]-8-methyl-
thiazolo[3,2-c]pyrimidine-5,7-dione;
6-(4-Methanesulfonyl-benzyl)-8-methyl-2-(3-pyridin-4-yl-prop-1-ynyl)-
thiazolo[3,2-c]pyrimidine-5,7-dione;
4-{ 2-[3-(3-Methoxy-phenyl)-prop-1-ynyl]-8-methyl-5,7-dioxo-7H-
thiazolo[3,2-c]pyrimidin-6-ylmethyl }-benzonitrile;
4-[8-Methyl-5,7-dioxo-2-(3-phenyl-prop-l -ynyl)-7H-thiazolo[3,2-
c]pyrimidin-6-ylmethyl]-benzoic acid;
2-[3-(3-Methoxy-phenyl)-prop-1-ynyl]-8-methyl-6-[4-(2H-tetrazol-5-yl)-
benzyl]-thiazolo[3,2-c]pyrimidine-5,7-dione;
6-Benzyl-2-[3-(3-methoxy-phenyl)-prop-1-ynyl]-8-methyl-thiazolo[3,2-
c]pyrimidine-5,7-dione;
6-Benzyl-8-methyl-2-(3-phenyl-prop-1-ynyl)-thiazolo[3,2-c]pyrimidine-
5,7-dione;
2-[3-(3-Methoxy-phenyl)-prop-1-ynyl]-8-methyl-6-[4-(morpholine-4-
carbonyl)-benzyl]-thiazolo[3,2-c]pyrimidine-5,7-dione;
8-Methyl-6-[4-(morpholine-4-sulfonyl)-benzyl]-2-(3-pyridin-4-yl-prop-1-
ynyl)-thiazolo[3,2-c]pyrimidine-5,7-dione;
2-[3-(4-Fluoro-phenyl)-prop-1-ynyl]-8-methyl-6-(2-oxo-2H-1-
benzopyran-6-ylmethyl)-thiazolo[3,2-c]pyrimidine-5,7-dione;
2-[3-(3-Methoxy-phenyl)-prop-1-ynyl]-8-methyl-6-(2-oxo-2H-1-
benzopyran-6-ylmethyl)-thiazolo[3,2-c]pyrimidine-5,7-dione;
4-[8-Methyl-5,7-dioxo-2-(4-phenyl-but-1-ynyl)-7H-thiazolo[3,2-
c]pyrimidin-6-ylmethyl]-benzoic acid;
4-[8-Methyl-5,7-dioxo-2-(6-phenyl-hex-1-ynyl)-7H-thiazolo[3,2-
c]pyrimidin-6-ylmethyl]-benzoic acid;
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4-[8-Methyl-5,7-dioxo-2-(5-phenyl-pent-1-ynyl)-7H-thiazolo[3,2-
c]pyrimidin-6-ylmethyl]-benzoic acid;
4-[8-Methyl-5,7-dioxo-2-(7-phenyl-hept-1-ynyl)-7H-thiazolo[3,2-
c]pyrimidin-6-ylmethyl]-benzoic acid;
(4-{ 2-[3-(3,4-Difluoro-phenyl)-prop-1-ynyl]-8-methyl-5,7-dioxo-7H-
thiazolo[3,2-c]pyrimidin-6-ylmethyl }-phenyl)-acetic acid;
6-(3-Fluoro-benzyl)-8-methyl-2-(3-pyridin-4-yl-prop-1-ynyl)-thiazolo[3,2-
c]pyrimidine-5,7-dione;
6-(3,4-Dif7uoro-benzyl)-8-methyl-2-(3-pyridin-4-yl-prop-1-ynyl)-
thiazolo[3,2-c]pyrimidine-5,7-dione;
6-(3-Fluoro-benzyl)-2-[3-(2-methoxy-pyridin-4-yl)-prop-1-ynyl]-8-
methyl-thiazolo[3,2-c]pyrimidine-5,7-dione;
[3-(8-Methyl-5,7-dioxo-2-phenylethynyl-7H-thiazolo[3,2-c]pyrimidin-6-
ylmethyl)-phenyl]-acetic acid;
~ 6-(4-Bromo-benzyl)-2-[3-(4-fluoro-3-methoxy-phenyl)-prop-1-ynyl]-8-
methyl-thiazolo[3,2-c]pyrimidine-5,7-dione;
4-{ 2-[3-(3-Methoxy-phenyl)-prop-1-ynyl]-8-methyl-5,7-dioxo-7H-
thiazolo[3,2-c]pyrimidin-6-ylmethyl } -N,N-dimethyl-benzenesulfonamide;
4-{ 2-[3-(3-Fluoro-4-methoxy-phenyl)-prop-1-ynyl]-8-methyl-5,7-dioxo-
7H-thiazolo[3,2-c]pyrimidin-6-ylmethyl }-cyclohexanecarboxylic acid;
6-(3,4-Difluoro-benzyl)-2-[3-(3,4-difluoro-phenyl)-prop-1-ynyl]-8-methyl-
thiazolo[3,2-c]pyrimidine-5,7-dione;
4-[8-Methyl-5,7-dioxo-2-(3-phenyl-prop-1-ynyl)-7H-thiazolo[3,2-
c]pyrimidin-6-ylmethyl]-cyclohexanecarboxylic acid;
2-Chloro-4-{2-[3-(3-methoxy-phenyl)-prop-1-ynyl]-8-methyl-5,7-dioxo-
7H-thiazolo[3,2-c]pyrimidin-6-ylmethyl }-benzoic acid;
2-[3-(4-Fluoro-phenyl)-prop-1-ynyl]-6-(4-methanesulfonyl-benzyl)-8-
methyl-thiazolo[3,2-c]pyrimidine-5,7-dione;
4-{ 2-[3-(4-Fluoro-3-methoxy-phenyl)-prop-1-ynyl]-8-methyl-5,7-dioxo-
7H-thiazolo[3,2-c]pyrimidin-6-ylmethyl }-benzonitrile;
(3-{ 2-[3-(4-Fluoro-3-methoxy-phenyl)-prop-1-ynyl]-8-methyl-5,7-dioxo-
7H-thiazolo[3,2-c]pyrimidin-6-ylmethyl }-phenyl)-acetic acid;
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(4-{ 2-[3-(3-Methoxy-phenyl)-prop-1-ynyl]-8-methyl-5,7-dioxo-7H-
thiazolo[3,2-c]pyrimidin-6-ylmethyl }-phenyl)-acetic acid;
6-(3,4-Difluoro-benzyl)-8-methyl-2-(3-phenyl-prop-l -ynyl)-thiazolo[3,2-
c]pyrimidine-5,7-dione;
2-[3-(3-Methoxy-phenyl)-prop-1-ynyl]-8-methyl-6-[4-(thiomorpholine-4-
carbonyl)-benzyl]-thiazolo[3,2-c]pyrimidine-5,7-dione;
8-Methyl-2-(3-pyri di n-4-yl-prop-1-ynyl)-6-[4-(thiomorphol ine-4-
sulfonyl)-benzyl]-thiazolo[3,2-c]pyrimidine-5,7-dione;
2-[3-(4-Fluoro-3-methoxy-phen yl )-prop-1-yn yl ]-8-methyl-6-(2-oxo-2H-1-
benzopyran-6-ylmethyl)-thiazolo[3,2-c]pyrimidine-5,7-dione; and
2-[3-(3-Methoxy-4-methyl-phenyl)-prop-l -ynyl]-8-methyl-6-(2-oxo-2H-1-
benzopyran-6-ylmethyl)-thiazolo[3,2-c]pyrimidine-5,7-dione, or a
pharmaceutically acceptable salt thereof.
14. The combination according to Embodiment l, wherein the compound of
Formula I is a compound selected from:
6-Benzoyl-thiazolo[3,2-c]pyrimidine-5,7-dione;
6-(4-Chlorobenzyl)-thiazolo[3,2-c]pyrimidine-5,7-dione;
6-Pyridin-4-ylmethyl-thiazolo]3,2-c]pyrimidine-5,7-dione;
8-Methyl-thiazolo[3,2-c]pyrimidine-5,7-dione;
8-Methyl-5,7-dioxo-6,7-dihydro-SH-thiazolo[3,2-c]pyrimidine-2-
carboxylic acid;
6-Benzyl-8-methyl-5,7-dioxo-6,7-dihydro-SH-thiazolo[3,2-c]pyrimidine-
2-carboxylic acid;
4-(8-methyl-5,7-dioxo-7H-thiazolo[3,2-c]pyrimidin-6-yl-methyl)-benzoic
acid tert-butyl ester; and
8-Methyl-6-[4-(Morpholine-4-sulfonyl)benzyl]-thiazolo[3,2-c]pyrimidine-
5,7-dione, or a pharmaceutically acceptable salt thereof.
15. The combination according to Embodiment l, wherein the compound of
Formula I is selected from:
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8-Methyl-5,7-dioxo-6-(3-oxo-3-phenyl-propyl)-6,7-dihydro-SH-
thiazolo[3,2-c]pyrimidine-2-carboxylic acid 4-fluoro-benzylamide;
8-Methyl-6-(1-phenylethyl) 5,7-dioxo-6,7-dihydro-SH-thiazolo[3,2-
c]pyrimidine-2-carboxylic acid 4-fluorobenzylamide;
8-Methyl-5,7-dioxo-6-(2-phenylmethanesulfonyl-ethyl)-6,7-dihydro-SH-
thiazolo[3,2-c]pyrimidine-2-carboxylic acid 4-fluorobenzylamide;
6-(5-Cyano-pentyl)-8-Methyl-5,7-dioxo-6,7-dihydro-SH-thiazolo[3,2-
c]pyrimidine-2-carboxylic acid 4-fluorobenzylamide;
6-(E)-But-2-enyl-8-Methyl-5,7-dioxo-6,7-dihydro-SH-thiazolo[3,2-
c]pyrimidine-2-carboxylic acid 4-fluorobenzylamide;
8-Methyl-5,7-dioxo-6-(E)-pent-2-enyl-6,7-dihydro-SH-thiazolo[3,2-
c]pyrimidine-2-carboxylic acid 4-fluorobenzylamide;
6-sec-Butyl-8-Methyl-5,7-dioxo-6,7-dihydro-SH-thiazolo[3,2-
c]pyrimidine-2-carboxylic acid 4-fluorobenzylamide;
8-Methyl-6-(2-methyl-allyl)-5,7-dioxo-6,7-dihydro-SH-thiazolo[3,2-
c]pyrimidine-2-carboxylic acid 4-fluorobenzylamide;
6-( 1-Ethyl-propyl)-8-Methyl-5,7-dioxo-6,7-dihydro-SH-thiazolo[3,2-
c]pyrimidine-2-carboxylic acid 4-fluorobenzylamide;
8-Methyl-5,7-dioxo-6-pent-2-ynyl-6,7-dihydro-SH-thiazolo[3,2-
c]pyrimidine-2-carboxylic acid 4-fluorobenzylamide;
6-(2-Benzensulfonyl-ethyl)-8-Methyl-5,7-dioxo-6,7-dihydro-SH-
thiazolo[3,2-c]pyrimidine-2-carboxylic acid 4-fluorobenzylamide;
8-Methyl-6-(3-methyl-but-2-enyl)-5,7-dioxo-6,7-dihydro-SH-thiazolo[3,2-
c]pyrimidine-2-carboxylic acid 4-fluorobenzylamide;
6-[2-(4-Fluoro-benzensulfonyl)-ethyl]-8-Methyl-5, 7-dioxo-6,7-dihydro-
SH-thiazolo[3,2-c]pyrimidine-2-carboxylic acid 4-fluorobenzylamide;
6-[3-(4-Fluoro-phenyl)-3-oxo-propyl]-8-Methyl-5,7-dioxo-6,7-dihydro-
SH-thiazolo[3,2-c]pyrimidine-2-carboxylic acid 4-fluorobenzylamide;
8-Methyl-5,7-dioxo-6-} 2-[(1-phenyl-methanoyl)-amino]-ethyl }-6,7-
dihydro-SH-thiazolo[3,2-c]pyrimidine-2-carboxylic acid 4-fluorobenzylamide;
8-Methyl-5,7-dioxo-6-(2-phenoxy-ethyl)-6,7-dihydro-SH-thiazolo[3,2-
c]pyrimidine-2-carboxylic acid 4-fluorobenzylamide; and
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{ 5-[2-(4-Fluoro-benzylcarbamoyl)-8-methyl-5,7-dioxo-7H-thiazolo[3,2-
c]pyrimidine-6-ylmethyl]-isoxazol-3-yl] }-carbamic acid methyl ester, or a
pharmaceutically acceptable salt thereof.
16. A combination, comprising valdecoxib, or a pharmaceutically acceptable
salt thereof, and an allosteric carboxylic inhibitor of MMP-13 of Formula IA
R2
R3 R1
IA
B.C I / C.A
ii ii
E E
wherein R1, R2, and R3 independently are hydrogen, halo, hydroxy, C1-C6 alkyl,
C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, N02, NR4R5, CN, or CF3;
E is independently O or S;
A and B independently are OR4 or NR4R5;
each R4 and RS independently are H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6
alkynyl, (CH2)n aryl, (CH2)n cycloalkyl, (CH2)n heteroaryl, or R4 and RS
when taken together with the nitrogen to which they are attached complete
a 3- to 8-membered ring, optionally containing a heteroatom selected from
O, S, or NH, and optionally substituted or unsubstituted;
n is an integer from 0 to 6;
or a pharmaceutically acceptable salt thereof.
l7. The combination according to Embodiment 16, wherein the compound of
Formula IA is a compound of Formula IIA
R2
R3 R1
IIA
R40 ~ / OR4
i
O O
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or a pharmaceutically acceptable salt thereof,
wherein Rl, R2, and R3 are as defined above for Embodiment 16, and each R4
independently is as defined above for Embodiment 16.
18. The combination according to Embodiment 16, wherein the compound of
Formula IA is a compound of Formula IIIA
R2
R3 R1
IIIA
R4R5 -N ~ / N-R4R5
i
O O
or a pharmaceutically acceptable salt thereof,
wherein Rl, R2, and R3 are as defined above for Embedment 16, and each R4 and
RS independently are as defined above.
19. The combination according to Embodiment 16, wherein the compound of
Formula IA is a compound of Formula IVA
R2
R6 R3 Rl
Rg IVA
7 ~ ~CH2)n _O ~ / O-(CH2)n ~ 9
R ~' I I I R
or a pharmaceutically acceptable salt thereof,
wherein n, Rl, R2, and R3 are as defined above for Embodiment 16, and R6, R~,
R8, and R9 independently are hydrogen, halo, Cl-C6 alkyl, Cl-C6 alkoxy,
nitro, or NH2.
20. The combination according to Embodiment 16, wherein the compound of
Formula IA is a compound of Formula VA
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82
R3 ~ _R1
VA
Het-(CH2)n-O ~ / O-'(CH2)n-Het
or a pharmaceutically acceptable salt thereof,
wherein n, R1, R2, and R3 are as defined above for Embodiment 16, and Het is
an
unsubstituted or substituted heteroaryl group.
21. The combination according to Embodiment 16, wherein the compound of
Formula IA is a compound of Formula VIA
R2
R3 R1
VI
R40 \ ~ NR4R5
O O
or a pharmaceutically acceptable salt thereof,
wherein R1, R2, and R3 are as defined above for Embodiment 16, and each R4
and RS independently are as defined above for Embodiment 16.
22. The combination according to Embodiment 16, wherein the compound of
Formula IA is selected from:
4-Methoxy-N,N'-bis-(4-methoxybenzyl)-isophthalamide;
Isophthalic acid di-(2,1,3-benzothiadiazol-5-yl) methyl ester;
4-Methoxy-isophthalic acid dibenzyl ester;
4-Methoxy-isophthalic acid dipyridin-4-ylmethyl ester;
Isophthalic acid bis-(4-fluoro-benzyl) ester;
Isophthalic acid bis-(3-fluoro-benzyl) ester;
Isophthalic acid bis-(4-methoxy-benzyl) ester;
Isophthalic acid bis-(3-methoxy-benzyl) ester;
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Isophthalic acid bis-(1,3-benzodioxol-5-ylmethyl) ester;
N,N'-Bis-(3-f7uoro-benzyl)-isophthalamide;
4-Acetyl-isophthalic acid dibenzyl ester;
4-Methoxycarbonylmethoxy-isophthalic acid dibenzyl ester;
' N,N'-Bis-1,3-benzodioxol-5-ylmethyl-4-methoxy-isophthalamide;
N-1,3-Benzodioxol-5-yl methyl-4-methoxy-N'-(4-methoxy-benzyl)-
isophthalamide;
4-Methoxy-N,N'-bis-(4-methoxy-benzyl)-isophthalamide;
N-1,3-Benzodioxol-5-ylmethyl-N'-(4-chloro-benzyl)-4-methoxy-
isophthalamide;
N-Benzyl-4-methoxy-N'-(4-methoxy-benzyl)-isophthalamide;
N'-Benzyl-4-methoxy-N-(4-methoxy-benzyl)-isophthalamide;
4-Methoxy-N-(4-methoxy-benzyl)-N'-pyridin-4-ylmethyl-isophthalamide;
N'-1,3-Benzodioxol-5-ylmethyl-4-methoxy-N-(2-phenoxy-ethyl)-
isophthalamide;
N-1,3-Benzodioxol-5-ylmethyl-4-methoxy-N'-(2-phenoxy-ethyl)-
isophthalamide;
N-1,3-Benzodioxol-5-ylmethyl-N'-furan-2-ylmethyl-isophthalamide;
N'-1,3-Benzodioxol-5-ylmethyl-N-(2-ethoxy-ethyl)-4-methoxy-
isophthalamide;
N,N'-Bis-(3-hydroxymethyl-phenyl)-isophthalamide;
N-Benzyl-4-methoxy-N'-(2-phenoxy-ethyl)-isophthalamide;
4-Methoxy-N,N'-bis-(4-methyl-benzyl)-isophthalamide;
4-Methoxy-N,N'-bis-(3-methoxy-benzyl)-isophthalamide;
N-1,3-Benzodioxol-5-ylmethyl-4-methoxy-N'-(4-methoxy-benzyl)-
isophthalamide; .
N-1,3-Benzodioxol-5-ylmethyl-isophthalamic acid, (4-carboxyphenyl)
methyl ester;
4-{ [3-(3-Methoxy-benzylcarbamoyl)-benzoylamino]-methyl }-benzoic
acid;
4-Methoxy-isophthalic acid di-2,1,3-benzothiadiazol-5-ylmethyl ester;
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4-{ [3-(3-Methoxy-benzylcarbamoyl)-benzoylamino]-methyl }-benzoic acid
methyl ester;
N-(3-Methoxy-benzyl)-N'-(4-vitro-benzyl)-isophthalamide;
N-(3,4-Dichloro-benzyl)-N'-pyridin-4-ylmethyl-isophthalamide;
Nl,N3-Bis-1,3-benzodioxol-5-ylmethyl-4-ethoxy-isophthalamide;
N-(4-Chloro-benzyl)-N'-(3-methoxy-benzyl)-isophthalamide;
N-(3,4-Dichloro-benzyl)-N'-(3-methoxy-benzyl)-isophthalamide;
N-(4-Methoxy-benzyl)-N'-(3-methoxy-benzyl)-isophthalamide;
N,N'-Bis-(4-fluoro-3-methoxy-benzyl)-isophthalamide;
4-Ethoxy-N1,N3-bis-(3-methoxy-benzyl)-isophthalamide;
Nl ,N3-Bis-1,3-benzodioxol-5-ylmethyl-4-ethoxy-isophthalamide;
N-(3-Methoxy-benzyl)-N'-pyridin-3-ylmethyl-isophthalamide;
N-(3-Methoxy-benzyl)-N'-pyridin-4-ylmethyl-isophthalamide;
N 1- I ,3-Benzodioxol-5-ylmethyl-N3-pyridin-3-ylmethyl-isophthalamide;
N-(3-Methoxy-benzyl)-N'-(3-trifluoromethoxy-benzyl)-isophthalamide;
N 1,N3-Bis-1,3-benzodioxol-5-ylmethyl-4-isopropoxy-isophthalamide;
4-Isopropoxy-N 1,N3-bis-(3-methoxy-benzyl)-isophthalamide;
N 1-Benzyl-4-methoxy-N3-(4-methoxy-benzyl)-isophthalamide;
Nl -l ,3-Benzodioxol-5-ylmethyl-4-methoxy-N3-(4-methoxy-benzyl)-
isophthalamide;
N I -1,3-Benzodioxol-5-ylmethyl-4-methoxy-N3-(2-phenoxy-ethyl)-
isophthalamide;
Nl -Benzyl-4-methoxy-N3-(2-phenoxy-ethyl)-isophthalamide;
N 1-1,3-Benzodioxol-5-yl methyl-N3-(4-chloro-benzyl)-4-methoxy-
isophthalamide;
N3-1,3-Benzodioxol-5-yl methyl-4-methoxy-N 1-(4-methox y-benzyl)-
isophthalamide;
N3-Benzyl-4-methoxy-N 1-(4-methoxy-benzyl)-isophthalamide;
N3-1,3-Benzodioxol-5-yl methyl-4-methox y-N 1-(2-phenoxy-ethyl)-
isophthalamide;
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N3-1,3-Benzodioxol-5-yl methyl-N 1-(2-ethoxy-ethyl)-4-methoxy-
isophthalamide;
4-Methoxy-N 1-(4-methoxy-benzyl)-N3-pyridin-4-ylmethyl-
isophthalamide;
' 4-Amino-N1,N3-bis-l,3-benzodioxol-5-ylmethyl-isophthalamide;
4-Acetylamino-Nl,N3-bis-l,3-benzodioxol-5-ylmethyl-isophthalamide;
N-(3-Methoxy-benzyl)-N'-pyridin-3-ylmethyl-isophthalamide;
N-(3-Methoxy-benzyl)-N'-pyridin-4-ylmethyl-isophthalamide;
Nl-1,3-Benzodioxol-5-ylmethyl-N3-pyridin-3-ylmethyl-isophthalamide;
N-(4-Chloro-benzyl)-N'-(3-methoxy-benzyl)-isophthalamide;
N-(3,4-Dichloro-benzyl)-N'-(3-methoxy-benzyl)-isophthalamide;
N-(4-Methoxy-benzyl)-N'-(3-methoxy-benzyl)-isophthalamide;
N-(3-Methoxy-benzyl)-N'-(4-methyl-benzyl)-isophthalamide;
N,N'-Bis-(4-fluoro-3-methoxy-benzyl)-isophthalamide;
~ ({3-[(1,3-Benzodioxol-S-ylmethyl)-carbamoyl]-benzoyl}-benzyl-amino)-
acetic acid;
N-Benzo[ l ,3]dioxol-5-ylmethyl-isophthalamic(4-hydroxymethyl-benzoic
acid) ester;
N-(3,4-Dichloro-benzyl)-N'-pyridin-4-ylmethyl-isophthalamide;
N-(3-Methoxy-benzyl)-N'-(4-vitro-benzyl)-isophthalamide;
4-{ [3-(3-Methoxy-benzylcarbamoyl)-benzoylamino]-methyl }-benzoic acid
methyl ester;
N-3-Methoxybenzyl-isophthalamic(4-hydroxymethyl-benzoic acid) ester;
4-{ [3-(3-Methoxy-benzylcarbamoyl)-benzoylamino]-methyl }-benzoic
acid;
N-(3-Amino-benzyl)-N'-(3-methoxy-benzyl)-isophthalamide;
N-(3-Methoxy-benzyl)-N'-(3-vitro-benzyl)-isophthalamide;
4-Ethoxy-N'I,N"3-bis-(3-methoxy-benzyl)-isophthalamide;
Nl ,N3-Bis-l ,3-benzodioxol-5-ylmethyl-4-ethoxy-isophthalamide;
Nl,N3-Bis-1,3-benzodioxol-5-ylmethyl-4-propoxy-isophthalamide;
N 1,N3-Bis-1,3-benzodioxol-5-ylmethyl-4-i sopropoxy-i sophthalamide;
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N 1,N3-Bis-2,1,3-benzothiadiazol-5-ylmethyl-4-methoxy-isophthalamide;
and
4-Methoxy-isophthalic acid di-2,1,3-benzothiadiazol-5-ylmethyl ester, or a
pharmaceutically acceptable salt thereof.
23. A combination, comprising valdecoxib, or a pharmaceutically acceptable
salt thereof, and an allosteric carboxylic inhibitor of MMP-13 of Formula IB
Y
R ~N~Ni R4
Y
W
or a pharmaceutically acceptable salt thereof;
wherein:
W, together with the carbon atoms to which it is attached, form a 5-membered
ring diradical
/ X / ~X
N
R2 A-B-R3 , \A B-R3 ,
X .~ ~ ~ 3
R2 X A B-R
A-B-R3 ,
X ~ R2
R3 B- A X R2 or
' A-B-R3
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O (O)0-2
A is -C- or -S-;
B is O or NRS; or
A and B are taken together to form -C=C-;
X is O, S, SO, S02, NRS, or CH2;
each Y independently is O or S;
R1, R4, and RS independently are hydrogen, C1-C6 alkyl, C2-Cg alkenyl,
C2-C6 alkynyl, (CH2)n cycloalkyl, (CH2)n heterocyclic, C1-C6 alkanoyl,
(CH2)n aryl, or (CH2)n heteroaryl;
R2 and R3 independently are hydrogen, C1-C6 alkyl, C2-C6 alkenyl,
C2-C6 alkynyl, CN, N02, NR4R5, (CH2)n cycloalkyl, (CH2)n aryl, or
(CH2)n heteroaryl; CONR4R5, or CORE;
R2 may further be halo;
n is an integer of from 0 to 5;
R4 and RS when taken together with the nitrogen to which they are attached
complete a 3- to 8-membered ring containing carbon atoms and optionally
containing O, S, or N, and substituted or unsubstituted;
wherein R1 and R3 are not both selected from: hydrogen and C1-C6 alkyl.
24. The combination according to Embodiment 23, wherein the compound of
Formula IB is a compound of Formula IIB
Y
RvN~Ni R4
y~ /~S IIB
R2 A-B - R3
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or a pharmaceutically acceptable salt thereof, wherein A, B, Rl, R2, R3, R4,
and
Y are as defined above for Embodiment 23.
25. The combination according to Embodiment 23, wherein the compound of
Formula IB is a compound of Formula IIIB
O
1 ~ 4
R ~N Ni R
IIIB
R2 A-B - R3
or a pharmaceutically acceptable salt thereof, wherein A, B, Rl, R2, and R4
are as
defined above for Embodiment 23, and R3 is (CH2)n aryl, (CH2)n
cycloalkyl, or (CH2)n heteroaryl.
26. The combination according to Embodiment 23, wherein the compound of
Formula 1B is a compound of Formula IVB
O
1 ~ 4
R ~N Ni R
/ 'O IVB
R2 A-B - R3
or a pharmaceutically acceptable salt thereof, wherein A, B, Rl, R2, R3, and
R4
are as defined above for Embodiment 23.
27. The combination according to Embodiment 23, wherein the compound of
Formula IB is a compound of Formula VB
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O
1 ~ 4
R ~N N~ R .
p / N~ RS VB
R2 A-B - R3
or a pharmaceutically acceptable salt thereof, wherein A, B, Rl, R2, R3, R4,
and
RS are as defined above for Embodiment 23.
28. The combination according to Embodiment 23, wherein the compound of
Formula IB is a compound of Formulas VIB, VIIB, VIIIB, or IXB:
O
1 ~ 4
R ~N N, R
V IB
N
\A-B - R3
O
1 ~ 4
RAN NiR
pi~ ~N VIIB
S
A-B - R3
O
R ~N~N~ R4
p 1 \ A-B - R3 VIIIB
X
R2
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O
4
R ~N N~ R
R2 IXB
X
R3 -B - A
or a pharmaceutically acceptable salt thereof, wherein A, B, X, R1, R2, R3,
and
R4 are as defined above for Embodiment 23.
29. The combination according to Embodiment 23, wherein the compound of
Formula IB is a compound of Formula XB
Rl
A-B - R3 XB
R~
or a pharmaceutically acceptable salt thereof, wherein R1-R4, A, B, and X are
as
defined above for Embodiment 23.
30. The combination according to Embodiment 23, wherein the compound of
Formula IB is a compound of Formula XIB
Y
RvN~Ni R4
XIB
Y
W
or a pharmaceutically acceptable salt thereof,
wherein:
W, together with the carbon atoms to which it is attached, form a 5-membered
ring diradical
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~ ~X
R3
R2
each Y independently is O or S;
X is S, O, or NRS;
Rl, R4, and RS independently are hydrogen, Cl-C6 alkyl, C2-C6 alkenyl,
C2-C6 alkynyl, (CH2)n cycloalkyl, (CH2)n heterocyclic, Cl-C6 alkanoyl,
(CH2)n aryl, or (CH2)n heteroaryl;
R2 is hydrogen, Cl-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, CN, N02, NR4R5,
(CH2)n cycloalkyl, (CH2)n aryl, or (CH2)n heteroaryl;
R3 is hydrogen, halo, C1-C6 alkyl, C2-C6 alkenyl, CN, N02, NR4R5, (CH2)q
cycloalkyl, (CH2)q aryl, or (CH2)q heteroaryl;
' n is 0, 1, or 2;
g is 2, 3, or 4; and
R4 and RS when taken together with the nitrogen to which they are attached
complete a 3- to 8-membered ring containing carbon atoms and optionally
containing O, S, or N, and substituted or unsubstituted;
wherein R1 and R3 are not both selected from: hydrogen and C1-Cg alkyl.
31. The combination according to Embodiment 23, wherein the compound of
Formula 1B is selected from:
3-Benzyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-dJpyrimidine-
6-carboxylic acid benzyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid benzyl ester;
3-(4-Pyridyl)-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-dJpyrimidine-
6-carboxylic acid benzyl ester;
3-(4-Pyridyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]-
pyrimidine-6-carboxylic acid benzyl ester;
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3-Benzyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-dJpyrimidine-
6-carboxylic acid (4-pyridyl) ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid (4-pyridyl) ester;
3-(4-Pyridyl)-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid (4-pyridyl) ester;
3-(4-Pyridyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]-
pyrimidine-6-carboxylic acid (4-pyridyl) ester;
3-Benzyl-2,4-dioxo-l ,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid piperoyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid piperoyl ester;
3-Piperoyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid piperoyl ester;
3-Piperoyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]-
pyrimidine-6-carboxylic acid piperoyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-furo[2,3-d]pyrimidine-
6-carboxylic acid benzyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-1 H-pyrrolo[2,3-d]-
pyrimidine-6-carboxylic acid benzyl ester;
3-Benzyl-1,7-dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-1 H-pyrrolo[2,3-d]-
pyrimidine-6-carboxylic acid benzyl ester;
3-Benzyl-1,7-dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-1 H-pyrrolo[2,3-d]-
pyrimidine-6-carboxylic acid benzofuran-6-ylmethyl ester;
3-Benzyl-1-dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-1H-pyrrolo[2,3-d]-
pyrimidine-6-carboxylic acid benzofuran-6-ylmethyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-furo[2,3-dJpyrimidine-
6-carboxylic acid benzofuran-6-ylmethyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid benzofuran-6-ylmethyl ester;
3-Benzyl-1,7-dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-l H-pyrrolo[2,3-d]-
pyrimidine-6-carboxylic acid benzothiophene-6-ylmethyl ester;
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3-Benzyl-1-dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-1 H-pyrrolo[2,3-d]-
pyrimidine-6-carboxylic acid benzothiophene-6-ylmethyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-furo[2,3-d]pyrimidine-
6-carboxylic acid benzothiophene-6-ylmethyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid benzothiophene-6-ylmethyl ester;
3-(3-Methoxy-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid benzyl ester;
3-(4-Chloro-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid benzyl ester;
3-(4-Cyano-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid benzyl ester;
3-(4-Fluoro-benzyl)-1-methyl-2,4-dioxo-l ,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid benzyl ester;
3-(3-Chloro-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid benzyl ester;
1-Methyl-3-(2-methyl-benzyl)-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid benzyl ester;
l -Methyl-3-(4-methyl-benzyl)-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid benzyl ester;
3-(4-Carboxy-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid benzyl ester;
l -Methyl-2,4-dioxo-3-(3-trifluoromethyl-benzyl)-1,2,3,4-tetrahydro-
thieno[2,3-d]pyrimidine-6-carboxylic acid benzyl ester;
3-Biphenyl-4-ylmethyl-l-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid benzyl ester;
l -Methyl-2,4-dioxo-3-(2-trifluoromethyl-benzyl)-1,2,3,4-tetrahydro-
thieno[2,3-d]pyrimidine-6-carboxylic acid benzyl ester;
3-(3-Cyano-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrah ydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid benzyl ester;
3-(2-Cyano-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid benzyl ester;
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1-Methyl-2,4-dioxo-3-(4-trifluoromethyl-benzyl)-l ,2,3,4-tetrahydro-
thieno[2,3-d]pyrimidine-6-carboxylic acid benzyl ester;
3-[2-Hydroxy-3-(naphthalen-1-yloxy)-propyl]-1-methyl-2,4-dioxo-1,2,3,4-
tetrahydro-thieno[2,3-d]pyrimidine-6-carboxylic acid benzyl ester;
3-(3-Chloro-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid benzyl ester;
1-Methyl-3-naphthalen-1-ylmethyl-2,4-dioxo-1,2,3,4-tetrahydro-
thieno[2,3-d]pyrimidine-6-carboxylic acid benzyl ester;
3-(6-Chloro-benzo[ 1,3]dioxol-5-ylmethyl)-1-methyl-2,4-dioxo-1,2,3,4-
l0 tetrahydro-thieno[2,3-d]pyrimidine-6-carboxylic acid benzyl ester;
1-Methyl-2,4-dioxo-3-(4-oxo-4-thiophen-2-yl-butyl)-1,2,3,4-tetrahydro-
thieno[2,3-d]pyrimidine-6-carboxylic acid benzyl ester;
l -Methyl-2,4-dioxo-3-pyridin-4-ylmethyl-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid benzyl ester;
1-Methyl-2,4-dioxo-3-(4-m-tolyloxy-butyl)-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid benzyl ester;
3-(3,5-Dimethyl-isoxazol-4-ylmethyl)-1-methyl-2,4-dioxo-1,2,3,4-
tetrahydro-thieno[2,3-d]pyrimidine-6-carboxylic acid benzyl ester;
3-Dioxo-1,3-dihydro-isoindol-2-ylmethyl)-1-methyl-2,4-dioxo-1,2,3,4-
20 tetrahydro-thieno[2,3-d]pyrimidine-6-carboxylic acid benzyl ester;
3-Dihydro-benzo[ 1,4]dioxin-2-yl methyl)-1-methyl-2,4-dioxo-l ,2,3,4-
tetrahydro-thieno[2,3-d]pyrimidine-6-carboxylic acid benzyl ester;
l -Methyl-2,4-dioxo-3-pyridin-2-ylmethyl-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid benzyl ester;
25 3-[2-(2,5-Dimethoxy-phenyl)-2-oxo-ethyl]-1-methyl-2,4-dioxo-1,2,3,4-
tetrahydro-thieno(2,3-d]pyrimidine-6-carboxylic acid benzyl ester;
3-Benzyloxymethyl-l -methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid benzyl ester;
1-Methyl-2,4-dioxo-3-(4-m-tolyloxy-butyl)-1,2,3,4-tetrahydro-thieno[2,3-
30 d]pyrimidine-6-carboxylic acid benzyl ester;
1-Methyl-2,4-dioxo-3-(2-phenylmethanesulfonyl-ethyl)-1,2,3,4-
tetrahydro-thieno[2,3-d]pyrimidine-6-carboxylic acid benzyl ester;
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3-(4-Amino-6-phenylamino-[ 1,3,5]triazin-2-ylmethyl)-1-methyl-2,4-
dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-6-carboxylic acid benzyl
ester;
3-[4-(4-Fluoro-phenyl)-4-oxo-butyl]-1-methyl-2,4-dioxo-1,2,3,4-
tetrahydro-thieno[2,3-d]pyrimidine-6-carboxylic acid benzyl ester;
' 3-[4-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-butyl]-1-methyl-2,4-dioxo-
1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-6-carboxylic acid benzyl ester;
l -Methyl-2,4-dioxo-3-(4-phenoxy-butyl)-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid benzyl ester;
1-Methyl-2,4-dioxo-3-(4-oxo-4-phenyl-butyl)-1,2,3,4-tetrahydro-
thieno[2,3-d]pyrimidine-6-carboxylic acid benzyl ester;
1-Methyl-2,4-dioxo-3-(2-phenoxy-ethyl)-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid benzyl ester;
3-{ 3-[4-(3-Chloro-phenyl)-piperazin-l -yl]-propyl }-1-methyl-2,4-dioxo-
1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-6-carboxylic acid benzyl ester;
' 3-[l-Bromo-2-(1H-indol-3-yl)-ethyl]-1-methyl-2,4-dioxo-1,2,3,4-
tetrahydro-thieno[2,3-d]pyrimidine-6-carboxylic acid benzyl ester;
3-(2-Benzenesulfinyl-ethyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-
thieno[2,3-d]pyrimidine-6-carboxylic acid benzyl ester;
3-[3-(3-Fluoro-phenylcarbamoyl)-propyl]-1-methyl-2,4-dioxo-1,2,3,4-
tetrahydro-thieno[2,3-d]pyrimidine-6-carboxylic acid benzyl ester;
1-Methyl-2,4-dioxo-3-[2-(2-trifluoromethyl-phenylcarbamoyl)-ethyl]-
1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-6-carboxylic acid benzyl ester;
3-[2-(4-Methoxy-phenyl)-ethyl]-1-methyl-2,4-dioxo-l ,2,3,4-tetrahydro-
thieno[2,3-d]pyrimidine-6-carboxylic acid benzyl ester;
3-[2-(4-Chloro-2-vitro-phenoxy)-ethyl]-1-methyl-2,4-dioxo-1,2,3,4-
tetrahydro-thieno[2,3-d]pyrimidine-6-carboxylic acid benzyl ester;
l -Methyl-3-(5-vitro-furan-2-ylmethyl)-2,4-dioxo-1,2,3,4-tetrahydro-
thieno[2,3-d]pyrimidine-6-carboxylic acid benzyl ester;
3-(1-Benzyl-1 H-imidazol-2-ylmethyl)-1-methyl-2,4-dioxo-1,2,3,4-
tetrahydro-thieno[2,3-d]pyrimidine-6-carboxylic acid benzyl ester;
3-[3-(Benzyl-methyl-amino)-propyl]-1-methyl-2,4-dioxo-1,2,3,4-
tetrahydro-thieno[2,3-d]pyrimidine-6 -carboxylic acid benzyl ester;
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3-(Bis-trifluoromethyl-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-
thieno[2,3-d]pyrimidine-6-carboxylic acid benzyl ester;
3-[3-(2-Bromo-4-methyl-phenoxy)-propyl]-1-methyl-2,4-dioxo-1,2,3,4-
tetrahydro-thieno[2,3-d]pyrimidine-6-carboxylic acid benzyl ester;
3-Benzenesulfonylmethyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-
thieno[2,3-d]pyrimidine-6-carboxylic acid benzyl ester;
3-[2-(4-Chloro-benzenesulfonyl)-ethyl]-1-methyl-2,4-dioxo-1,2,3,4-
tetrahydro-thieno[2,3-d]pyrimidine-6-carboxylic acid benzyl ester;
3-Benzo[ 1,3Jdioxol-5-yl methyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-
thieno[2,3-d]pyrimidine-6-carboxylic acid benzyl ester;
3-(3-Iodo-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-
c~pyrimidine-6-carboxylic acid benzyl ester;
1-Methyl-2,4-diox o-3-(4-trifluoromethoxy-benzyl )-1,2,3,4-tetrahydro-
thieno[2,3-d]pyrimidine-6-carboxylic acid benzyl ester;
3-(4-Acetoxy-butyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid benzyl ester;
3-(4-Methanesulfonyl-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-
thieno[2,3-d]pyrimidine-6-carboxylic acid benzyl ester;
1-Methyl-2,4-dioxo-3-(4-[ 1,2,3]thi adiazol-4-yl-benzyl)-1,2,3,4-tetrahydro-
thieno[2,3-d]pyrimidine-6-carboxylic acid benzyl ester;
3-(5-Methoxycarbonyl-furan-2-ylmethyl)-1-methyl-2,4-dioxo-1,2,3,4-
tetrahydro-thieno[2,3-d]pyrimidine-6-carboxylic acid benzyl ester;
3-(2-Carboxy-ethyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid benzyl ester;
1-Methyl-2,4-dioxo-3-(3-pyrrol-l -yl-propyl)-1,2,3,4-tetrahydro-
thieno[2,3-d]pyrimidine-6-carboxylic acid benzyl ester;
3-(3-Carboxy-propyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-
dJpyrimidine-6-carboxylic acid benzyl ester;
3-(2-Cyano-ethyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid benzyl ester;
3-(3-Ethoxycarbonyl-furan-2-ylmethyl)-1-methyl-2,4-dioxo-1,2,3,4-
tetrahydro-thieno[2,3-d]pyrimidine-6-carboxylic acid benzyl ester;
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3-(3-Amino-propyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid benzyl ester;
3-(3-Cyano-propyl)-l -methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid benzyl ester;
' 3-(2-Hydroxy-ethyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid benzyl ester;
3-(2-Carboxy-hexyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid benzyl ester;
1-Methyl-2,4-dioxo-3-(2,2,2-trifluoro-ethyl)-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid benzyl ester;
1-Methyl-2,4-dioxo-3-(2,2,2-trifluoro-ethyl)-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxyl carboxylic acid benzyl ester;
Iodomethyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid benzyl ester;
3-(2-Fluoro-ethyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid benzyl ester;
Methyl-2,4-dioxo-3-(tetrahydro-furan-2-ylmethyl)-1,2,3,4-tetrahydro-
thieno[2,3-d]pyrimidine-6-carboxylic acid benzyl ester;
3-[ 1-(4-Carboxy-phenyl)-ethyl]-l -methyl-2,4-dioxo-1,2,3,4-tetrahydro-
thieno[2,3-d]pyrimidine-6-carboxylic acid benzyl ester;
3-(Hex-5-enyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid benzyl ester;
3-(2-Ethyl-butyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid benzyl ester;
1-Methyl-2,4-dioxo-3-(2,2,2-trifluoro-ethyl)-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxyl pyrimidine acid benzyl ester;
3-(Diethoxy-phosphorylmethyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-
thieno[2,3-d]pyrimidine-6-carboxylic acid benzyl ester;
3-But-2-ynyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid benzyl ester;
Bromo-ethyl)-1-methyl-2,4-dioxo-l ,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid;
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1-Methyl-2,4-dioxo-3-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1,2,3,4-
tetrahydro-thieno[2,3-d]pyrimidine-6-carboxylic acid benzyl ester;
1-Methyl-2,4-dioxo-3-propyl-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid benzyl ester;
3-(2-Acetoxy-ethyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid;
3-Butyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-6-
carboxylic acid benzyl ester;
3-Isobutyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
l0 6-carboxylic acid benzyl ester;
3-Ethyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-dJpyrimidine-6-
carboxylic acid benzyl ester;
3-(3-Bromo-propyl)-1-methyl-2,4-dioxo-l ,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid benzyl ester;
3-Cyclohexylmethyl-1-methyl-2,4-dioxo-7,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid benzyl ester;
3-(2-Ethylamino-ethyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid benzyl ester;
3-Cyclobutylmethyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid benzyl ester;
3-((R)-3-Hydroxy-2-methyl-propyl )-1-methyl-2,4-dioxo-1,2,3,4-
tetrahydro-thieno[2,3-d]pyrimidine-6-carboxylic acid benzyl ester;
3-(4-Hydroxy-butyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid benzyl ester;
3-(2-Ethoxy-ethyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-
c!]pyrimidine-6-carboxylic acid benzyl ester;
3-Isobutyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid benzyl ester;
3-(2-Chloro-ethyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid benzyl ester;
1-Methyl-3-(3-methyl-but-2-enyl)-2,4-dioxo-1,2,3,4-tetrahydro-
thieno[2,3-dJpyrimidine-6-carboxylic acid benzyl ester;
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3-Allyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-6-
carboxylic acid benzyl ester;
3-(2,2-Dimethoxy-ethyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-
thieno[2,3-d]pyrimidine-6-carboxylic acid benzyl ester;
1-Methyl-3-oxiranylmethyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-
d]p,yrimidine-6-carboxylic acid benzyl ester;
1-Methyl-2,4-dioxo-3-propyl-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid benzyl ester;
3-Benzo[ 1,2,5]oxadiazol-5-ylmethyl-1-methyl-2,4-dioxo-1,2,3,4-
tetrahydro-thieno[2,3-dJpyrimidine-6-carboxylic acid benzyl ester;
3-(3-Hydroxy-2,2-dimethyl-propyl)-1-methyl-2,4-dioxo-1,2,3,4-
tetrahydro-thieno[2,3-d]pyrimidine-6-carboxylic acid benzyl ester;
3-(2-Carboxy-ethyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid benzyl ester;
3-Propyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-dJpyrimidine-
6-carboxylic benzyl ester;
1-Methyl-2,4-dioxo-3-(4-sulfamoyl-benzyl)-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid benzyl ester;
1-Methyl-3-(4-methylsulfamoyl-benzyl)-2,4-dioxo-1,2,3,4-tetrahydro-
thieno[2,3-d]pyrimidine-6-carboxylic acid benzyl ester;
3-(4-Dimethylsulfamoyl-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-
thieno[2,3-d]pyrimidine-6-carboxylic acid benzyl ester;
3-(4-Methanesulfonylamino-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-
tetrahydro-thieno[2,3-d]pyrimidine-6-carboxylic acid benzyl ester;
3-[4-(Methanesulfonyl-methyl-amino)-benzyl]-1-methyl-2,4-dioxo-
1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-6-carboxylic acid benzyl ester;
3-(4-Acetylamino-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-
thieno[2,3-d]pyrimidine-6-carboxylic acid benzyl ester;
3-[4-(Acetyl-methyl-amino)-benzyl]-1-methyl-2,4-dioxo-1,2,3,4-
tetrahydro-thieno[2,3-d]pyrimidine-6-carboxylic acid benzyl ester;
3-(4-Dimethylamino-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-
thieno[2,3-dJpyrimidine-6-carboxy lic acid benzyl ester;
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l -Methyl-3-(4-methyl amino-benzyl)-2,4-dioxo-1,2,3,4-tetrahydro-
thieno[2,3-d]pyrimidine-6-carboxylic acid benzyl ester;
3-(4-Carbamoyl-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-
thieno[2,3-d]pyrimidine-6-carboxylic acid benzyl ester;
3-(4-Dimethylcarbamoyl-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-
thieno[2,3-d]pyrimidine-6-carboxylic acid benzyl ester;
3-(4-Carboxy-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid benzyl ester;
3-(4-Methoxycarbonyl-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-
l0 thieno[2,3-d]pyrimidine-6-carboxylic acid benzyl ester;
3-{ 4-[Bis-(2-hydroxy-ethyl)-amino]-benzyl } -1-methyl-2,4-dioxo-1,2,3,4-
tetrahydro-thieno[2,3-d]pyrimidine-6-carboxylic acid benzyl ester;
3-(3,5-Dimethoxy-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-
thieno[2,3-d]pyrimidine-6-carboxylic acid benzyl ester;
3-(4-tert-Butyl-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid benzyl ester;
1-Methyl-2,4-dioxo-3-(4-trifluoromethoxy-benzyl)-1,2,3,4-tetrahydro-
thieno[2,3-d]pyrimidine-6-carboxylic acid benzyl ester;
3-(4-Methanesulfonyl-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-
thieno[2,3-d]pyrimidine-6-carboxylic acid benzyl ester;
2,4-Dioxo-3-[1,3,4]thiadiazol-2-ylmethyl-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid benzyl ester;
3-Isoxazol-3-ylmethyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid benzyl ester;
3-Oxazol-2-ylmethyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid benzyl ester;
2,4-Dioxo-3-thiazol-2-ylmethyl-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid benzyl ester;
3-( 1 H-Imidazol-2-ylmethyl)-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid benzyl ester;
3-(1-Methyl-1 H-imidazol-2-ylmethyl)-2,4-dioxo-1,2,3,4-tetrahydro-
thieno[2,3-d]pyrimidine-6-carboxylic acid benzyl ester;
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3-( l -Methyl-1 H-pyrrol-2-ylmethyl)-2,4-dioxo-1,2,3,4-tetrahydro-
thieno[2,3-d]pyrimidine-6-carboxylic acid benzyl ester;
2,4-Dioxo-3-( 1 H-pyrrol-2-ylmethyl)-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid benzyl ester;
2,4-Dioxo-3-( 1 H-pyrrol-2-ylmethyl)-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid benzyl ester;
2,4-Dioxo-3-thiophen-2-ylmethyl-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid benzyl ester;
2,4-Dioxo-3-[ 1,2,3,4]tetrazin-5-ylmethyl-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid benzyl ester;
2,4-Dioxo-3-[ 1,2,4,5]tetrazin-3-ylmethyl-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid benzyl ester;
3-( 1-Methyl-piperidin-4-yl methyl)-2,4-dioxo-1,2,3,4-tetrahydro-
thieno[2,3-d]pyrimidine-6-carboxylic acid benzyl ester;
2,4-Dioxo-3-pyrimidin-2-ylmethyl-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid benzyl ester;
2,4-Dioxo-3-(2H-pyran-2-ylmethyl)-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid benzyl ester;
3-( 1 H-Imidazo[4,5-b]pyridin-2-ylmethyl)-2,4-dioxo-1,2,3,4-tetrahydro-
thieno[2,3-d]pyrimidine-6 -carboxylic acid benzyl ester;
3-( 1 H-Benzoimidazol-2-ylmethyl)-2,4-dioxo-1,2,3,4-tetrahydro-
thieno[2,3-d]pyrimidine-6-carboxylic acid benzyl ester;
3-Benzo[b]thiophen-2-ylmethyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid benzyl ester;
2,4-Dioxo-3-quinolin-2-ylmethyl-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid benzyl ester;
3-(2H-Chromen-2-ylmethyl)-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid benzyl ester;
3-( 1 H-Benzoimidazol-2-ylmethyl)-2,4-dioxo-l ,2,3,4-tetrahydro-
thieno[2,3-d]pyrimidine-6-carboxylic acid benzyl ester;
3-( l -Methyl-1 H-benzoimidazol-2-ylmethyl)-2,4-dioxo-1,2,3,4-tetrahydro-
thieno[2,3-dJpyrimidine-6-carboxylic acid benzyl ester;
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3-( 1 H-Indol-2-ylmethyl)-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid benzyl ester;
3-Benzyl-I -methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid furan-3-ylmethyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-dJpyrimidine-
6-carboxylic acid 1-ethyl-propyl ester;
3-Benzyl-I -methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid l,l-dioxo-tetrahydro-ll6-thiophen-3-yl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 4-hydroxy-benzyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 1-oxy-pyridin-4-ylmethyl ester;
3-Benzyl-l -methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid but-3-enyl ester;
3-Benzyl-I-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 3-diethylamino-propyl ester;
3-Benzyl-1-methyl-2,4-dioxo-l ,2,3,4-tetrahydro-thieno[2,3-dJpyrimidine-
6-carboxylic acid 1-cyano-1-phenyl-methyl ester;
3-Benzyl-l -methyl-2,4-dioxo-l ,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 3-amino-benzyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 3-methoxy-benzyl ester;
3-Benzyl-l -methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 1-oxy-pyr idin-3-ylmethyl ester;
3-Benzyl-l-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 2-ethoxy-ethyl ester;
3-Benzyl-1-methyl-2,4-dioxo-I ,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid thiophen-2-ylmethyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-dJpyrimidine-
6-carboxylic acid 2,6-dichloro-benzyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid dimethylamino-methyl-ethyl ester;
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3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 2,2-Biphenyl-ethyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 2-pyridin -2-yl-ethyl ester;
' 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 2-ethanesulfonyl-ethyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-dJpyrimidine-
6-carboxylic acid diethylamino-methyl-ethyl ester;
3-Benzyl-1-methyl-2,4-dioxo-I ,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid dimethylamino-methyl-propyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-dJpyrimidine-
6-carboxylic acid 2-(2-chloro-phenoxy)-ethyl ester;
3-Benzyl-l -methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 2-(2-ethoxy-ethoxy)-ethyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 2-hydroxy-benzyl ester;
1-Methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-6-
carboxylic acid 2-morpholin-4-yl-ethyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 1-methyl-piperidin-4-yl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-dJpyrimidine-
6-carboxylic acid 2-(4-hydroxy-phenyl)-ethyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 2-cyano-ethyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid hexyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 4-fluoro-benzyl ester;
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3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 3-hydroxy-6-methyl-pyridin-2-ylmethyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 2-benzyloxy-ethyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 2-methoxy-benzyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 4-methoxy-benzyl ester;
3-Benzyl-l -methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 2,2,2-trifluoro-ethyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 2,2,2-trichloro-ethyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid pyridin-3-ylmethyl ester;
3-Benzyl-l-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid pyridin-4-ylmethyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 3-pyridin-3-yl-propyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 2-phenoxy-ethyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 1,3-dimethyl-butyl ester;
3-Benzyl-I-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 2-methyl-benzyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 1-phenyl-ethyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 1-benzyl-piperidin-4-yl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid propyl ester;
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3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid methyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-dJpyrimidine-
6-carboxylic acid 2-trifluoromethyl-benzyl ester;
' 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 2 p-tolyl-ethyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 4-trifluoromethyl-benzyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-dJpyrimidine-
6-carboxylic acid tetrahydro-furan-2-ylmethyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid octahydro-inden-5-yl ester;
3-Benzyl-l -methyl-2,4-dioxo-l ,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 4-amino-benzyl ester;
~ 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 2-aziridin-1-yl-ethyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-dJpyrimidine-
6-carboxylic acid 3-methyl-but-2-enyl ester;
3-Benzyl-l -methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid benzyl ester;
3-Benzyl-l -methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid trifluoro-trifluoromethyl-ethyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid phenethyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 2-methoxy-ethyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-dJpyrimidine-
6-carboxylic acid biphenyl-4-ylmethyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-dJpyrimidine-
6-carboxylic acid 2-chloro-6-fluoro-benzyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid tetrahydro-pyran-4-yl ester;
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3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 3-ethyl-oxetan-3-ylmethyl ester;
3-Benzyl-l -methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid butyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 2-(2-hydroxy-phenyl)-ethyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 2-(4-fluoro-phenyl)-ethyl ester;
3-Benzyl-1-methyl-2,4-dioxo-I ,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid cyclopropylmethyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic. acid 4-ethyl-benzyl ester;
3-Benzyl-I -methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid (S)-1-phenyl-ethyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 2,6-difluoro-benzyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid cyclobutyl methyl ester;
3-Benzyl-l -methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 2-pyridin-4-yl-ethyl ester;
3-Benzyl-l -methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 3-hydroxy-cyclopentyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 1-pentafluorophenyl-ethyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-dJpyrimidine-
6-carboxylic acid 2-benzyloxycarbonylamino-ethyl ester; and
3-Benzyl-1-methyl-2,4-dioxo-l ,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid ethyl ester; or a pharmaceutically acceptable salt thereof.
32. The combination according to Embodiment 23, wherein the compound of
Formula IB is selected from:
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3-Benzyl-l -methyl-2,4-dioxo-l ,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid (2-pyridin-4-yl-ethyl)-amide;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid (2-morpholin-4-yl-ethyl)-amide;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 4-methyl-benzylamide;
3-Benzyl-l -methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid sec-butylamide;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid cyclopentylamide;
3-Benzyl-l -methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid cyclopropylamide;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid cyanomethyl-amide;
3-Benzyl-l-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid cyclohexylamide;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 3-methyl-benzylamide;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid (3-ethoxy-propyl)-amide;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 2-chloro-benzylamide;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 2-methyl-benzylamide;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid (2,2-diphenyl-ethyl)-amide;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid (pyridin-3-ylmethyl)-amide;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid cyclopropylmethyl-amide;
3-Benzyl-l -methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid (l-ethyl-pyrrolidin-2-ylmethyl)-amide;
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3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid (pyridin-2-ylmethyl)-amide;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno(2,3-d]pyrimidine-
6-carboxylic acid [2-(3,4-dimethoxy-phenyl)-ethyl]-amide;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-dJpyrimidine-
6-carboxylic acid (furan-2-ylmethyl)-amide;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 2-fluoro-benzylamide;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid (2-bromo-ethyl)-amide;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 4-sulfamoyl-benzylamide;
3-Benzyl-1-methyl-2,4-dioxo-l ,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 3-methoxy-benzylamide;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 4-methoxy-benzylamide;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid phenethyl-amide;
(S)-2-{ [ 1-(3-Benzyl-l -methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidin-6-yl)-methanoyl]-amino}-propionic acid;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid (1-phenyl-ethyl)-amide;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 2-methoxy-benzylamide;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid benzylamide;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 3-bromo-benzylamide;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid [2-(4-sulfamoyl-phenyl)-ethyl]-amide;
2-{ [ 1-(3-Benzyl-1-methyl-2,4-dioxo-l ,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidin-6-yl)-methanoyl]-amino}-3-phenyl-propionic acid methyl ester;
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3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid (3-imidazol-1-yl-propyl)-amide;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-dJpyrimidine-
6-carboxylic acid [2-(2-methoxy-phenyl)-ethyl]-amide;
' 3-Benzyl-l-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 4-trifluoromethyl-benzylamide;
3-Benzyl-1-methyl-2,4-dioxo-l ,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 4-amino-benzylamide;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid [2-(4-fluoro-phenyl)-ethyl]-amide; and
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid ((R)-2-hydroxy-1-methyl-ethyl)-amide; or a pharmaceutically
acceptable salt thereof.
75 33: The combination according to Embodiment 23, wherein the compound of
Formula IB is selected from:
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid benzofuran-5-ylmethyl ester;
(3-{ [ 1-(3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidin-6-yl)-methanoyl]-amino}-propyl)-carbamic acid tert-butyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid benzofuran-2-ylmethyl ester;
3-Benzyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-~pyrimidine-6-
carboxylic acid thiophen-3-ylmethyl ester;
3-Benzyl-l-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 3H-[1,2,3]oxathiazol-5-ylmethyl ester;
3-Benzyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-6-
carboxylic acid 3H-[1,2,3]oxathiazol-5-ylmethyl ester;
3-Benzyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-6-
carboxylic acid [1,4,2]dioxazol-3-ylmethyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid [1,4,2]dioxazol-3-ylmethyl ester;
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3-Benzyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-6-
carboxylic acid furazan-3-ylmethyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid furazan-3-ylmethyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid [1,2,4]oxadiazol-5-ylmethyl ester;
3-Benzyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-dJpyrimidine-6-
carboxylic acid [1,2,4]oxadiazol-5-ylmethyl ester;
3-Benzyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-6-
carboxylic acid 3H-[1,2,3]triazol-4-ylmethyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 3H-[1,2,3]triazol-4-ylmethyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 2H-[1,2,4]triazol-3-ylmethyl ester;
3-Benzyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-6-
carboxylic acid 2H-[1,2,4]triazol-3-ylmethyl ester;
3-Benzyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-6-
carboxylic acid isoxazol-5-ylmethyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid isoxazol-5-ylmethyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-dJpyrimidine-
6-carboxylic acid oxazol-2-ylmethyl ester;
3-Benzyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-6-
carboxylic acid oxazol-2-ylmethyl ester;
3-Benzyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-6-
carboxylic acid isothiazol-5-ylmethyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid isothiazol-5-ylmethyl ester;
3-Benzyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-6-
carboxylic acid thiazol-2-ylmethyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid thiazol-2-ylmethyl ester;
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3-Benzyl-l -methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 1H-imidazol-2-ylmethyl ester;
3-Benzyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-6-
carboxylic acid 2H-imidazol-2-ylmethyl ester;
3-Benzyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-6-
carboxylic acid 1H-pyrazol-3-ylmethyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-dJpyrimidine-
6-carboxylic acid 2H-pyrazol-3-ylmethyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid lH-pyrrol-2-ylmethyl ester;
3-Benzyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-6-
carboxylic acid 2H-pyrrol-2-ylmethyl ester;
3-Furazan-3-ylmethyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid benzyl ester;
' 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 2H-chromen-2-ylmethyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 2H-thiochromen-2-ylmethyl ester;
3-Benzyl-2,4-dioxo-I ,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-6-
carboxylic acid 2H-thiochromen-2-ylmethyl ester;
3-Benzyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-6-
carboxylic acid [1,3,4]thiadiazol-2-ylmethyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid [1,3,4]thiadiazol-2-ylmethyl ester;
3-Benzyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-6-
carboxylic acid 1H-benzoimidazol-S-ylmethyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 1H-benzoimidazol-5-ylmethyl ester;
3-Benzyl-l -methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 1H-benzoimidazol-2-ylmethyl ester;
3-Benzyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-dJpyrimidine-6-
carboxylic acid 1H-benzoimidazol-2-ylmethyl ester;
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3-Benzyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-6-
carboxylic acid 1H-indol-2-ylmethyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-dJpyrimidine-
6-carboxylic acid 1H-indol-2-ylmethyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-dJpyrimidine-
6-carboxylic acid 1H-indol-5-ylmethyl ester;
3-Benzyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-6-
carboxylic acid IH-indol-5-ylmethyl ester;
3-Benzyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-6-
carboxylic acid 2,3-dihydro-benzofuran-5-ylmethyl ester; and
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 2,3-dihydro-benzofuran-5-ylmethyl ester; or a
pharmaceutically
acceptable salt thereof.
34. The combination according to Embodiment 23, wherein the compound of
Formula IB is selected from:
4-{ 6-[3-(4-Methoxy-phenyl)-prop-1-ynyl]-1-methyl-2,4-dioxo-1,4-
dihydro-2H-thieno[2,3-d]pyrimidine-3-ylmehtyl}-benzoic acid;
3-(4-Methanesulfonyl-benzyl)-6-[3-(4-methoxy-phenyl)-prop-1-ynyl]-1-
methyl-lH-thieno[2,3-d]pyrimidine-2,4-dione;
4-{ 6-[3-(3-Methoxy-phenyl)-prop-1-ynyl]-1-methyl-2,4-dioxo-1,4-
dihydro-2H-thieno[2,3-d]pyrimidine-3-ylmehtyl }-benzoic acid;
3-(4-Methanesulfonyl-benzyl)-6-[3-(3-methoxy-phenyl)-prop-1-ynyl]-1-
methyl-l H-thieno[2,3-d]pyrimidine-2,4-dione;
4-[1-Methyl-2,4-dioxo-6-(3-pyridine-4-yl-prop-1-ynyl)-1,4-dihydro-2H-
thieno[2,3-d]pyrimidine-3-ylmehtyl]-benzoic acid;
3-(4-Methanesulfonyl-benzyl)-l -6-(3-pyridin-4-yl-prop-1-ynyl)-1 H-
thieno[2,3-d]pyrimidine-2,4-dione;
4-[ 1-Methyl-2,4-dioxo-6-(3-pyridine-3-yl-prop-1-ynyl)-1,4-dihydro-2H-
thieno[2,3-d]pyrimidine-3-ylmehtyl]-benzoic acid;
3-(4-Methanesulfonyl-benzyl)-1-6-(3-pyridin-3-yl-prop-1-ynyl)-1 H-
thieno[2,3-d]pyrimidine-2,4-dione;
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4-{ 6-[3-(4-Fluoro-phenyl)-prop-1-ynyl]-I -methyl-2,4-dioxo-1,4-dihydro-
2H-thieno[2,3-d]pyrimidine-3-ylmehtyl }-benzoic acid
6-[3-(4-Fluoro-phenyl)-prop-1-ynyl]-3-(4-methanesulfonyl-benzyl)-1-
methyl-l H-thieno[2,3-d]pyrimidine-2,4-dione;
4- { 6-[3-(3-Fluoro-phenyl)-prop-1-ynyl]-1-methyl-2,4-dioxo-1,4-dihydro-
2H-thieno[2,3-d]pyrimidine-3-ylmehtyl }-benzoic acid;
6-[3-(3-Fluoro-phenyl)-prop-1-ynyl]-3-(4-methanesulfonyl-benzyl)-1-
methyl-1 H-thieno[2,3-d]pyrimidine-2,4-dione;
4-{ 6-[3-(4-Chloro-phenyl)-prop-1-ynyl]-1-methyl-2,4-dioxo-I ,4-dihydro-
2H-thieno[2,3-d]pyrimidine-3-ylmehtyl }-benzoic acid;
6-[3-(4-Chloro-phenyl)-prop-I-ynyl]-3-(4-methanesulfonyl-benzyl)-1-
methyl-1 H-thieno[2,3-d]pyrimidine-2,4-dione;
4-{ 6-[3-(3-Chloro-phenyl)-prop-1-ynyl]-1-methyl-2,4-dioxo-1,4-dihydro-
2H-thieno[2,3-d]pyrmidine-3-ylmehtyl }-benzoic acid;
IS 6-[3-(3-Chloro-phenyl)-prop-1-ynyl]-3-(4-methanesulfonyl-benzyl)-1-
methyl-1H-thieno[2,3-d]pyrimidine-2,4-dione;
4-{ 6-[3-(4-Bromo-phenyl)-prop- 1-ynyl]-1-methyl-2,4-dioxo-1,4-dihydro-
2H-thieno[2,3-d]pyrimidine-3-ylmehtyl }-benzoic acid;
6-[3-(4-Bromo-phenyl)-prop-1-ynyl]-3-(4-methanesulfonyl-benzyl)-1-
methyl-1H-thieno[2,3-d]pyrimidine-2,4-dione;
4-{ 6-[3-(3-Bromo-phenyl)-prop-1-ynyl]- I -methyl-2,4-dioxo-1,4-dihydro-
2H-thieno[2,3-d]pyrimidine-3-ylmehtyl }-benzoic acid;
6-[3-(3-Bromo-phenyl)-prop-1-ynyl]-3-(4-methanesulfonyl-benzyl)-1-
methyl-1 H-thieno[2,3-d]pyrimidine-2,4-dione;
4-{ 1-Methyl-6-[3-(4-vitro-phenyl)-prop-1-ynyl]-2,4-dioxo-1,4-dihydro-
2H-thieno[2,3-d]pyrimidine-3-ylmehtyl}-benzoic acid;
3-(4-Methanesulfonyl-benzyl)-1-methyl-6-[3-(4-vitro-phenyl)-prop-1-
ynyl)-1 H-thieno[2,3-d]pyrimidine-2,4-dione;
4-{ 6-[3-(2-Methoxy-pyridin-4-yl)-prop-1-ynyl]-I -methyl-2,4-dioxo-1,4-
dihydro-2H-thieno[2,3-d]pyrimidine-3-ylmehtyl }-benzoic acid;
3-(4-Methanesulfonyl-benzyl)-6-[3-(2-methoxy-pyridin-4-yl)-prop-I-
ynyl]-I -methyl-1 H-thieno[2,3-d]pyrimidine-2,4-dione;
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4-{ 1-Methyl-6-[3-(4-methylsulfanyl-phenyl)-prop-1-ynyl]-2,4-dioxo-1,4-
dihydro-2H-thieno[2,3-d]pyrimidine-3-ylmehtyl }-benzoic acid;
3-(4-Methanesulfonyl-benzyl)-1-methyl-6-[3-(4-methylsulfanyl-phenyl)-
prop-1-ynyl]-1 H-thieno[2,3-d]pyrimidine-2,4-dione;
4-{ 1-Methyl-6-[3-(3-methylsulfanyl-phenyl)-prop-1-ynyl]-2,4-dioxo-1,4-
dihydro-2H-thieno[2,3-d]pyrimidine-3-ylmehtyl }-benzoic acid;
3-(4-Methanesulfonyl-benzyl)-1-methyl-6-[3-(3-methylsulfanyl-phenyl)-
prop-1-ynyl]-1 H-thieno[2,3-d]pyrimidine-2,4-dione;
4-[ 1-Methyl-2,4-di oxo-6-(3-p-tol yl-prop-1-ynyl)-1,4-di hydro-2H-
l0 thieno[2,3-d]pyrimidin-3-ylmethyl]benzoic acid;
3-(4-Methanesul fonyl-benzyl)-1-methyl-6-(3-p-tolyl-prop-1-yn yl )- l H-
thieno[2,3-d]pyrimidine-2,4-dione;
4-[ 1-Methyl-2,4-di ox o-6-(3-m-tol yl-prop-1-ynyl )-1,4-di hydro-2H-
thieno[2,3-d]pyrimidin-3-ylmethyl]benzoic acid;
l5 3-(4-Methanesulfonyl-benzyl)-1-methyl-6-(3-m-tolyl-prop-1-ynyl)-1H-
thieno[2,3-d]pyrimidine-2,4-dione;
3-Benzyl-6-[3-(4-methoxy-phenyl)-prop-1-ynyl]-1-methyl-I H-thieno[2,3-
dJpyrimidine-2,4-dione;
3-Benzyl-6-[3-(3-methoxy-phenyl )-prop-1-ynyl]-1-methyl-1 H-thieno[2,3-
20 d]pyrimidine-2,4-dione;
3-Benzyl-1-methyl-6-(3-pyridin-4-yl-prop-1-ynyl)-1 H-thieno[2,3-
d]pyrimidine-2,4-dione;
3-Benzyl-1-methyl-6-(3-pyridin-3-yl-prop-1-ynyl)-1 H-thieno[2,3-
d]pyrimidine-2,4-dione;
25 3-Benzyl-6-[3-(4-fluoro-phenyl)-prop-1-ynyl]-1-methyl-1H-thieno[2,3-
d]pyrimidine-2,4-dione;
3-Benzyl-6-[3-(3-fluoro-phenyl)-prop-l -ynyl]-l -methyl-1 H-thieno[2,3-
d]pyrimidine-2,4-dione;
3-Benzyl-6-[3-(4-chloro-phenyl)-prop-1-ynyl]-1-methyl-1 H-thieno[2,3-
30 dJpyrimidine-2,4-dione;
3-Benzyl-6-[3-(3-chloro-phenyl)-prop-1-ynyl]-1-methyl-1 H-thieno[2,3-
d]pyrimidine-2,4-dione;
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3-Benzyl-6-[3-(4-bromo-phenyl)-prop-1-ynyl]-1-methyl-1 H-thieno[2,3-
d]pyrimidine-2,4-dione;
3-Benzyl-6-[3-(3-bromo-phenyl)-prop-1-ynyl]-1-methyl-1 H-thieno[2,3-
d]pyrimidine-2,4-dione;
3-Benzyl-6-[3-(2-methoxy-pyridin-4-yl)-prop-1-ynyl]-1-methyl-1 H-
thieno[2,3-dJpyrimidine-2,4-dione;
3-Benzyl-1-methyl-6-[3-(4-methylsulfanyl-phenyl)-prop-1-ynyl]-1 H-
thieno[2,3-d]pyrimidine-2,4-dione;
3-Benzyl-l -methyl-6-[3-(3-methylsulfanyl-phenyl)-prop-1-ynyl]-l H-
thieno[2,3-d]pyrimidine-2,4-dione;
3-Benzyl-1-methyl-6-(3-p-tolyl-prop-1-ynyl)-1 H-thieno[2,3-d]pyrimidine-
2,4-dione;
3-Benzyl-1-methyl-6-(3-m-tol yl-prop-1-ynyl)-1 H-thieno[2,3-
d]pyrimidine-2,4-dione;
3-(3-Fluoro-benzyl)-6-[3-(4-methoxy-phenyl)-prop-1-ynyl]-1-methyl-1H-
thieno[2,3-d]pyrimidine-2,4-dione;
3-(3-Fluoro-benzyl)-6-[3-(3-methoxy-phenyl)-prop-1-ynyl]-1-methyl-1 H-
thieno[2,3-d]pyrimidine-2,4-dione;
3-(3-Fluoro-benzyl)-1-methyl-6-(3-pyridine-4-yl-prop-1-ynyl)-1 H-
thieno[2,3-d]pyrimidine-2,4-dione;
3-(3-Fluoro-benzyl)-1-methyl-6-(3-pyridine-3-yl-prop-1-ynyl)-1 H-
thieno[2,3-d]pyrimidine-2,4-dione;
3-(3-Fluoro-benzyl)-6-[3-(4-fluoro-phenyl)-prop-1-ynyl]-l -methyl-1 H-
thieno[2,3-d]pyrimidine-2,4-dione;
3-(3-Fluoro-benzyl)-6-[3-(3-fluoro-phenyl)-prop-1-ynyl]-1-methyl-1H-
thieno[2,3-d]pyrimidine-2,4-dione;
6-[3-(4-Chloro-phenyl)-prop-1-ynyl]-3-(3-fluoro-benzyl)-1-methyl-1 H-
thieno[2,3-d]pyrimidine-2,4-dione;
6-[3-(3-Chloro-phenyl)-prop-1-ynyl]-3-(3-fluoro-benzyl)-1-methyl-1 H-
thieno[2,3-d]pyrimidine-2,4-dione;
6-[3-(4-Bromo-phenyl)-prop-1-ynyl]-3-(3-fluoro-benzyl)-1-methyl-1H-
thieno[2,3-d]pyrimidine-2,4-dione;
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6-[3-(3-Bromo-phenyl)-prop-1-ynyl]-3-(3-fluoro-benzyl)-1-methyl-1 H-
thieno[2,3-d]pyrimidine-2,4-dione;
3-(3-Fluoro-benzyl)-6-[3-(2-methoxy-pyridin-4-yl)-prop-1-ynyl]-1-
methyl-1H-thieno[2,3-d]pyrimidine-2,4-dione;
3-(3-Fluoro-benzyl)-1-methyl-6-[3-(4-methylsulfanyl-phenyl)-prop-1-
ynyl]-1 H-thieno[2,3-d]pyrimidine-2,4-dione;
3-(3-Fluoro-benzyl)-l -methyl-6-[3-(3-methylsulfanyl-phenyl)-prop-1-
ynyl]-I H-thieno[2,3-d]pyrimidine-2,4-dione;
3-(3-Fluoro-benzyl)-1-methyl-6-(3-p-tolyl-prop-1-ynyl)-1 H-thieno[2,3-
d]pyrimidine-2,4-dione; and
3-(3-Fluoro-benzyl)-1-methyl-6-(3-m-tolyl-prop-1-ynyl)-1H-thieno(2,3-
d]pyrimidine-2,4-dione; or a pharmaceutically acceptable salt thereof.
35. The combination according to Embodiment 23, wherein the compound of
Formula IB is selected from:
3-(3-Methoxycarbonyl-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-
thieno[2,3-d]pyrimidine-6-carboxylic acid benzyl ester;
3-(3-Methoxycarbonyl-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-
thieno[2,3-d]pyrimidine-6-carboxylic acid benzyl ester;
3-Benzofuran-5-ylmethyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-
thieno[2,3-d]pyrimidine-6-carboxylic acid benzyl ester;
l -Methyl-3-(4-methyl-benzyl)-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid benzyl ester;
3-(4-Acetylamino-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-
thieno[2,3-d]pyrimidine-6-carboxylic acid benzyl ester;
1-Methyl-2,4-dioxo-3-(4-vinyl-benzyl)-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid benzyl ester;
1-Methyl-2,4-dioxo-3-(4-sulfamoyl-benzyl)-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid benzyl ester;
3-(4-Bromo-benzyl)-2,4-dioxo-1,2,3,4-tetrahydro-thieno(2,3-
d]pyrimidine-6-carboxylic acid pyridin-4-ylmethyl ester;
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1-Methyl-2,4-dioxo-3-phenethyl-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid benzyl ester;
1-Methyl-2,4-dioxo-3-[4-(2H-tetrazol-5-yl)-benzyl]-1,2,3,4-tetrahydro-
thieno[2,3-dJpyrimidine-6-carboxylic acid benzyl ester;
3-(4-Fluoro-benzyl)-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid pyridin-4-ylmethyl ester;
3-(4-tert-Butyoxycarbonyl-benzyl)-1-methy12,4-dioxo-1,2,3,4-tetrahydro-
thieno[2,3-d]pyrimidine-6-carboxylic acid benzyl ester;
3-(4-tert-Butyoxycarbonyl-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-
thieno[2,3-d]pyrimidine-6-carboxylic acid;
4-[6-(4-Fluoro-benzylcarbamoyl)-1-methyl-2;4-dioxo-1,4-dihydro-2H-
thieno[2,3-d]pyrimidin-3-ylmethyl]-benzoic acid;
4-[6-(4-Dimethylamino-benzylcarbamoyl)-1-methyl-2,4-dioxo-1,4-
dihydro-2H-thieno[2,3-d]pyrimidin-3-ylmethyl]-benzoic acid, compound with
l5 trifluoro-acetic acid;
4-[6-(2-Ethoxy-benzylcarbamoyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-
thieno[2,3-d]pyrimidine-3-ylmethyl]-benzoic acid;
l -Methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-6-
carboxylic acid;
1-Methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-6-
carboxylic acid 3-methoxy-benzylamide;
1-Methyl-2,4-dioxo-3-[4-( 1 H-tetrazol-5-yl)-benzyl]-1,2,3,4-tetrahydro-
thieno[2,3-d]pyrimidine-6-carboxylic acid 3-methoxy-benzylamide;
1-Methyl-3-[4-(morphol ine-4-sulfonyl)-benzyl]-2,4-dioxo-1,2,3,4-
tetrahydro-thieno[2,3-d]pyrimidine-6-carboxylic acid 3-methoxy-benzylamide;
1-Methyl-3-[4-(morpholine-4-carbonyl)-benzyl]-2,4-dioxo-1,2,3,4-
tetrahydro-thieno[2,3-d]pyrimidine-6-carboxylic acid 3-methoxy-benzylamide;
3-But-2-ynyl-1-methyl-2,4-dioxo-l ,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid 3-methoxy-benzylamide;
1-Methyl-2,4-dioxo-3-[3-( 1 H-tetrazol-5-yl)-benzyl]-1,2,3,4-tetrahydro-
thieno[2,3-d]pyrimidine-6-carboxylic acid 3-methoxy-benzylamide;
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3-(4-Cyano-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid 3-methoxy-benzylamide;
{ 4-[6-(3-Methoxy-benzylcarbamoyl)-1-methyl-2,4-dioxo-1,4-dihydro-2H-
thieno[2,3-d]pyrimidin-3-ylmethyl]-phenyl }-acetic acid;
3-[2-(2,4-Dichloro-benzenesulfonyl)-ethyl]-1-methyl-2,4-dioxo-1,2,3,4-
tetrahydro-thieno[2,3-d]pyrimidine-6-carboxylic acid 3-methoxy-benzylamide;
3-(4-Methanesul fon yl-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-
thieno[2,3-d]pyrimidine-6-carboxylic acid 3-methoxy-benzylamide;
1-Methyl-2,4-dioxo-3-(4-sulfamoyl-benzyl)-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid 3-methoxy-benzylamide;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid (2-methoxy-pyridin-4-ylmethyl)-amide;
1-Methyl-3-(4-methylsulfamoyl-benzyl)-2,4-dioxo-1,2,3,4-tetrahydro-
thieno[2,3-d]pyrimidine-6-carboxylic acid 3-methoxy-benzylamide;
IS 3-(4-Isopropylsulfamoyl-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-
thieno[2,3-d]pyrimidine-6-carboxylic acid 3-methoxy-benzylamide;
1-Methyl-2,4-dioxo-3-[4-(pyrrolidine-1-sulfonyl)-benzyl]-1,2,3,4-
tetrahydro-thieno[2,3-dJpyrimidine-6-carboxylic acid 3-methoxy-benzylamide;
and
1-Methyl-3-[4-(4-methyl-piperidine-1-sulfonyl)-benzyl]-2,4-dioxo-1,2,3,4-
tetrahydro-thieno[2,3-d]pyrimidine-6-carboxylic acid 3-methoxy-benzylamide; or
a pharmaceutically acceptable salt thereof.
36. The combination according to Embodiment 23, wherein the compound of
Formula IB is selected from:
3-Benzyl-l -methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid benzofuran-2-ylmethyl ester;
3-(4-Bromo-benzyl)-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid pyridin-4-ylmethyl ester;
3-Benzyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-6-
carboxylic acid 4-methoxy-benzyl ester;
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4-{ I-Methyl-2,4-dioxo-6-[(pyridin-4-ylmethyl)-carbamoyl]-1,4-dihydro-
2H-thieno[2,3-d]pyrimidin-3-ylmethyl}-benzoic acid, compound with trifluoro-
acetic acid;
4-[6-(4-Methoxy-benzylcarbamoyl)-I -methyl-2,4-dioxo-1,4-dihydro-2H-
thieno[2,3-d]pyrimidin-3-ylmethyl]-benzoic acid;
4-[6-(3,4-Di methox y-benzylcarbamoyl )-1-methyl-2,4-diox o-1,4-di hydro-
2H-thieno[2,3-d]pyrimidin-3-ylmethyl]-benzoic acid tert-butyl ester;
4-[6-(3,4-Di methoxy-benzylcarbamoyl)-I -methyl-2,4-dioxo-1,4-dihydro-
2H-thieno[2,3-d]pyrimidin-3-ylmethyl]-benzoic acid;
4-[6-(4-Bromo-benzylcarbamoyl)-1-methyl-2,4-dioxo-1,4-dihydro-2H-
thieno[2,3-d]pyrimidin-3-ylmethyl]-benzoic acid;
4-[6-(4-Bromo-benzylcarbamoyl)-1-methyl-2,4-dioxo-I ,4-dihydro-2H-
thieno[2,3-d]pyrimidin-3-ylmethyl]-benzoic acid tert-butyl ester;
4-[6-(3,5-Bis-trifluoromethyl-benzylcarbamoyl)-1-methyl-2,4-dioxo-1,4-
I S dihydro-2H-thieno[2,3-d]pyrimidin-3-ylmethyl]-benzoic acid;
4-[6-(4-Chloro-benzylcarbamoyl)-l -methyl-2,4-dioxo-1,4-dihydro-2H-
thieno[2,3-d]pyrimidin-3-ylmethyl]-benzoic acid;
4-[ 1-Methyl-2,4-dioxo-6-(4-sulfamoyl-benzylcarbamoyl)-1,4-dihydro-2H-
thieno[2,3-d]pyrimidin-3-ylmethyl]-benzoic acid;
3-(4-Fluoro-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid 4-methoxy-benzylamide;
3-(4-Iodo-benzyl)-l -methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid 3-methoxy-benzylamide;
3-(4-Dimethylsulfamoyl-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-
thieno[2,3-d]pyrimidine-6-carboxylic acid 4-methoxy-benzylamide;
3-(3-Methoxy-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid 4-methoxy-benzylamide;
3-(4-Cyano-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid 4-methoxy-benzylamide;
3-(4-Acetylamino-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-
thieno[2,3-d]pyrimidine-6-carboxylic acid 3-methoxy-benzylamide;
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5-[6-(3-Methoxy-benzylcarbamoyl)-l -methyl-2,4-dioxo-1,4-dihydro-2H-
thieno[2,3-d]pyrimidin-3-ylmethyl]-furan-2-carboxylic acid ethyl ester;
3-(4-Cyano-benzyl)-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 3-methoxy-benzyl ester;
' 1-Methyl-2,4-dioxo-3-[4-(5-thioxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-
benzyl]-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-6-carboxylic acid 4-methoxy-
benzylamide;
4-[6-(3-Methoxy-benzylcarbamoyl)-1-methyl-2,4-dioxo-1,4-dihydro-2H-
thieno[2,3-d]pyrimidin-3-ylmethyl]-benzoic acid 2-dimethylamino-ethyl ester;
3-Cyclohexylmethyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid 4-methoxy-benzylamide;
3-Cyclohexylmethyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid 4-methoxy-benzylamide;
3-Benzyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-6-
carboxylic acid furan-3-ylmethyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid pentafluorophenylmethyl ester;
3-Benzyl-1-ethyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-6-
carboxylic acid benzyl ester;
3-Benzyl-1-cyclopropylmethyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid benzyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid (pyridin-4-ylmethyl)-amide;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 3-bromo-benzyl ester;
4-[6-(3-Difluoromethoxy-benzylcarbamoyl)-1-methyl-2,4-dioxo-1,4-
dihydro-2H-thieno[2,3-d]pyrimidin-3-ylmethyl]-benzoic acid;
4-[6-(3-Difluoromethoxy-benzylcarbamoyl)-1-methyl-2,4-dioxo-1,4-
dihydro-2H-thieno[2,3-d]pyrimidin-3-ylmethyl]-benzoic acid tert-butyl ester;
4-[6-(3-Methoxy-benzylcarbamoyl)-1-methyl-2,4-dioxo-1,4-dihydro-2H-
thieno[2,3-d]pyrimidin-3-ylmethyl]-benzoic acid;
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4-[6-(4-Methanesulfonyl-benzylcarbamoyl)-1-methyl-2,4-dioxo-1,4-
dihydro-2H-thieno(2,3-d]pyrimidin-3-ylmethyl]-benzoic acid tert-butyl ester;
4-[6-(4-Methanesulfonyl-benzylcarbamoyl)-1-methyl-2,4-dioxo-1,4-
dihydro-2H-thieno[2,3-d]pyrimidin-3-ylmethyl]-benzoic acid;
4-[l-Methyl-2,4-dioxo-6-(2-pyridin-4-yl-ethylcarbamoyl)-1,4-dihydro-2H-
thieno[2,3-d]pyrimidin-3-ylmethyl]-benzoic acid;
1-Methyl-2,4-dioxo-3-(4-trifluoromethoxy-benzyl)-1,2,3,4-tetrahydro-
thieno[2,3-d]pyrimidine-6-carboxylic acid 3-methoxy-benzylamide;
4-[6-(3-Methoxy-benzylcarbamoyl)-1-methyl-2,4-dioxo-1,4-dihydro-2H-
thieno[2,3-d]pyrimidin-3-ylmethyl]-benzoic acid methyl ester;
3-(2,3-Dihydro-benzofuran-6-ylmethyl)-1-methyl-2,4-dioxo-1,2,3,4-
tetrahydro-thieno[2,3-d]pyrimidine-6-carboxylic acid 3-methoxy-benzylamide;
1-Methyl-3-(2-methyl-thiazol-5-ylmethyl)-2,4-dioxo-1,2,3,4-tetrahydro-
thieno[2,3-d]pyrimidine-6-carboxylic acid 3-methoxy-benzylamide;
1-Methyl-2,4-dioxo-3-[4-( 1 H-tetrazol-5-yl)-benzyl]-1,2,3,4-tetrahydro-
thieno[2,3-d]pyrimidine-6-carboxylic acid 4-fluoro-benzylamide;
3-Benzyl-2-methoxy-4-oxo-3,4-dihydro-thieno[2,3-d]pyrimidine-6-
carboxylic acid benzyl ester;
4-[6-(3-Methoxy-benzylcarbamoyl)-1-methyl-2,4-dioxo-1,4-dihydro-2H-
thieno[2,3-d]pyrimidin-3-ylmethyl]-benzoic acid 2,2-dimethyl-
propionyloxymethyl ester;
4-[6-(3-Methoxy-benzylcarbamoyl)-1-methyl-2,4-dioxo-1,4-dihydro-2H-
thieno[2,3-d]pyrimidin-3-ylmethyl]-cyclohexanecarboxylic acid;
4-[6-(3-Methoxy-benzylcarbamoyl)-1-methyl-2,4-dioxo-1,4-dihydro-2H-
thieno[2,3-d]pyrimidin-3-ylmethyl]-cyclohexanecarboxylic acid methyl ester;
1-{ 4-[6-(3-Methoxy-benzylcarbamoyl)-1-methyl-2,4-dioxo-1,4-dihydro-
2H-thieno[2,3-d]pyrimidin-3-ylmethyl]-phenyl }-cyclopropanecarboxylic acid
methyl ester;
1-{4-[6-(3-Methoxy-benzylcarbamoyl)-1-methyl-2,4-dioxo-1,4-dihydro-
2H-thieno[2,3-d]pyrimidin-3-ylmethyl]-phenyl }-cyclopropanecarboxylic acid
tert-
butyl ester;
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1- { 4-[6-(3-Methoxy-benzylcarbamoyl)-1-methyl-2,4-dioxo-l ,4-dihydro-
2H-thieno[2,3-d]pyrimidin-3-ylmethyl]-phenyl}-cyclopropanecarboxylic acid;
2-{ 4-[6-(3-Methoxy-benzylcarbamoyl)-1-methyl-2,4-dioxo-1,4-dihydro-
2H-thieno[2,3-d]pyrimidin-3-ylmethyl]-phenoxy}-2-methyl-propionic acid tert-
butyl ester;
2-{ 4-[6-(3-Methoxy-benzylcarbamoyl)-1-methyl-2,4-dioxo-1,4-dihydro-
2H-thieno[2,3-d]pyrimidin-3-ylmethyl]-phenoxy}-2-methyl-propionic acid;
3-Benzyl-1-methyl-2,4-d ioxo-1,2,3,4-tetrahydro-furo[2,3-d]pyrimidine-6-
carboxylic acid benzyl ester;
3-(3-Methoxy-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid benzyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid benzyl ester;
3-Biphenyl-4-ylmethyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid benzyl ester;
3-(4-Methanesulfonyl-benzyl)-l -methyl-2,4-dioxo-1,2,3,4-tetrahydro-
thieno[2,3-d]pyrimidine-6-carboxylic acid benzyl ester;
3-(4-Methanesulfonyl-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-
thieno[2,3-d]pyrimidine-6-carboxylic acid benzyl ester;
l -Methyl-3-(4-methyl-benzyl)-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid benzyl ester;
1-Methyl-2,4-dioxo-3-phenethyl-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid benzyl ester;
3-(4-Amino-6-phenylamino-1,3,5-triazin-2-ylmethyl)-1-methyl-2,4-dioxo-
1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-6-carboxylic acid benzyl ester;
l -Methyl-2,4-dioxo-3-(4-trifluoromethyl-benzyl)-1,2,3,4-tetrahydro-
thieno[2,3-d]pyrimidine-6-carboxylic acid benzyl ester;
3-(6-Cyano-hexyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid benzyl ester;
3-[2-(2,5-Dimethoxy-phenyl)-2-oxo-ethyl]-1-methyl-2,4-dioxo-1,2,3,4-
tetrahydro-thieno[2,3-d]pyrimidine-6-carboxylic acid benzyl ester;
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3-(3-Iodo-bepzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid benzyl ester;
1-Methyl-2,4-dioxo-3-(3-trifluoromethyl-benzyl)-1,2,3,4-tetrahydro-
thieno[2,3-d]pyrimidine-6-carboxylic acid benzyl ester;
3-(2,4-Bis-trifluoromethyl-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-
thieno[2,3-d]pyrimidine-6-carboxylic acid benzyl ester;
3-[2-( 1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-ethyl]-1-methyl-2,4-dioxo-
1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-6-carboxylic acid benzyl ester;
3-[2-( 1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-ethyl]-1-methyl-2,4-dioxo-
l0 1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-6-carboxylic acid benzyl ester;
3-(2-Carboxy-allyl )-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid benzyl ester;
3-(2-Carboxy-allyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid benzyl ester;
15 3-(3-Amino-propyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid benzyl ester;
3-( 1,3-Dioxo-1,3-dihydro-isoindol-2-ylmethyl)-1-methyl-2,4-dioxo-
1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-6-carboxylic acid benzyl ester;
3-(4-Fluoro-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-
20 d]pyrimidine-6-carboxylic acid benzyl ester;
1-Methyl-3-oxiranylmethyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid benzyl ester;
1-Methyl-3-((S)-2-methyl-butyl)-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid benzyl ester;
25 1-Methyl-2,4-dioxo-3-(4-phenoxy-butyl)-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid benzyl ester;
3-(2-Cyano-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid benzyl ester;
1-Methyl-2,4-dioxo-3-(3-phenoxy-propyl)-1,2,3,4-tetrahydro-thieno[2,3-
30 d]pyrimidine-6-carboxylic acid benzyl ester;
3-Hex-5-enyl-1-methyl-2,4-dioxo-l ,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid benzyl ester;
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1-Methyl-2,4-dioxo-3-pyridin-3-ylmethyl-7 ,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid benzyl ester;
3-[2-Hydroxy-3-(naphthalen-1-yloxy)-propyl]-1-methyl-2,4-dioxo-1,2,3,4-
tetrahydro-thieno[2,3-d]pyrimidine-6-carboxylic acid benzyl ester;
' l,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-6-
carboxylic acid benzyl ester;
3-Cyclobutylmethyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid benzyl ester;
3-Allyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-6-
carboxylic acid benzyl ester;
I -Methyl-2,4-dioxo-3-prop-2-ynyl-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid benzyl ester;
3-But-2-ynyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid benzyl ester;
~ 1-Methyl-2,4-dioxo-3-(2-phenoxy-ethyl)-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid benzyl ester;
1-Methyl-2,4-dioxo-3-(2-phenoxy-ethyl)-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid benzyl ester;
3-((R)-3-Hydroxy-2-methyl-propyl)-1-methyl-2,4-dioxo-1,2,3,4-
tetrahydro-thieno[2,3-d]pyrimidine-6-carboxylic acid benzyl ester;
3-Isobutyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid benzyl ester;
3-(6-Chloro-pyridin-3-ylmethyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-
thieno[2,3-d]pyrimidine-6-carboxylic acid benzyl ester;
3-(2-Benzenesulfonylmethyl-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-
tetrahydro-thieno[2,3-d]pyrimidine-6-carboxylic acid benzyl ester;
1-Methyl-3-naphthalen-l -ylmethyl-2,4-dioxo-1,2,3,4-tetrahydro-
thieno[2,3-d]pyrimidine-6-carboxylic acid benzyl ester;
1-Methyl-2,4-dioxo-3-(2-tri f7uoromethyl-benzyl)-1,2,3,4-tetrahydro-
thieno[2,3-d]pyrimidine-6-carboxylic acid benzyl ester;
3-(3-Chloro-benzyl)-1-methyl-2,4-dioxo-l ,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid benzyl ester;
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3-(4-Methoxycarbonyl-butyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-
thieno[2,3-d]pyrimidine-6-carboxylic acid benzyl ester;
3-Ethyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-6-
carboxylic acid benzyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 4-fluoro-benzyl ester;
3-[2-(4-Chloro-benzenesulfonyl)-ethyl]-1-methyl-2,4-dioxo-1,2,3,4-
tetrahydro-thieno[2,3-d]pyrimidine-6-carboxylic acid benzyl ester;
3-(2-Acetoxy-ethyl)-I -methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid benzyl ester;
3-Benzyl-l -methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 2-phenoxy-ethyl ester;
3-Benzyl-1-methyl-2,4-dioxo-l ,2,3,4-tetrahydro-thieno[2,3-dJpyrimidine-
6-carboxylic acid benzyl ester;
IS 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-dJpyrimidine-
6-carboxylic acid benzylamide;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 2,6-dichloro-benzyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid butyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 2,3-dihydro-1,4-benzodioxin-2-ylmethyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 2-diethylamino-1-methyl-ethyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 4-fluoro-benzyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-dJpyrimidine-
6-carboxylic acid 4-isopropyl-benzyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 2-p-tolyl-ethyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 4-trifluoromethyl-benzyl ester;
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3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid cyclobutylmethyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid.2,6-difluoro-benzyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 2-(2-hydroxy-phenyl)-ethyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 2-(2-hydroxy-phenyl)-ethyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 1-methyl-piperidin-4-yl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid l-methyl-piperidin-4-yl ester;
3-Benzyl-l -methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid pyridin-3-ylmethyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 3-pyridin-3-yl-propyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 2-dimethylamino-1-methyl-ethyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 4-methoxy-benzyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid tetrahydro-pyran-4-yl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 2,2,2-trifluoro-1-trifluoromethyl-ethyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 2-trifluoromethyl-benzyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 2-benzyloxy-ethyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 2,2,2-trichloro-ethyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyri midine-
6-carboxylic acid phenethyl ester;
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3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 3-ethyl-oxetan-3-ylmethyl ester;
3-Benzyl-1-methyl-2,4-dioxo-l ,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 2-morpholin-4-yl-ethyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 2-pyrrolidin-1-yl-ethyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 2-pyrrolidin-1-yl-ethyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 2-(2-ethoxy-ethoxy)-ethyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid tetrahydro-pyran-2-ylmethyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 4-nitro-benzyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid pentyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 3-phenyl-propyl ester;
3-Benzyl-1-methyl-2,4-dioxo-l ,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 3-phenoxy-benzyl ester;
3-Benzyl-1-methyl-2,4-dioxo-l ,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 3,5-dimethoxy-benzyl ester;
3-Benzyl-1-methyl-2,4-dioxo-l ,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 3-methyl-butyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 4-chloro-benzyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 1-ethyl-piperidin-3-yl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 4-benzyloxy-benzyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid isobutyl ester;
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3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 3-(4-methoxy-phenyl)-propyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 2-chloro-6-fluoro-benzyl ester;
' 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid (S)-(tetrahydro-furan-3-yl) ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 3-methoxy-benzyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 3-methoxy-benzyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 3-pyridin-2-yl-propyl ester;
3-Benzyl-1-methyl-2,4-dioxo-l ,2,3,4-tetrahydro-thieno[2,3-d] pyrimidine-
6-carboxylic acid 2-piperidin-2-yl-ethyl ester;
IS 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 5-bromo-2-methoxy-benzyl ester;
3-Benzyl-l -methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid cycloheptylmethyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 1,2,3,4-tetrahydro-naphthalen-1-yl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid (S)-1-pyrrolidin-2-ylmethyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 3-chloro-benzyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 1,3-benzodioxol-5-ylmethyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 4-methylsulfanyl-benzyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 4-methylsulfanyl-benzyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 3,4-dichloro-benzyl ester;
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3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 3,3-Biphenyl-propyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 2-pyridin-2-yl-ethyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid furan-3-ylmethyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid but-3-enyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 2-cyano-ethyl ester;
3-Benzyl-1-methyl-2,4-dioxo-l ,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 2-ethoxy-ethyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid cyano-phenyl-methyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 4-trifluoromethyl-benzylamide;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 4-methyl-benzylamide;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid phenethyl-amide;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid cyclopropylamide;
1-Methyl-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-6-carboxylic acid 4-
methoxy-benzylamide;
1-Methyl-2,4-dioxo-3-(4-sulfamoyl-benzyl)-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid 4-methoxy-benzylamide;
1-Methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-6-
carboxylic acid3-methoxy-benzylamide;
1-Methyl-2,4-dioxo-3-(3-oxo-3-phenyl-propyl)-1,2,3,4-tetrahydro-
thieno[2,3-d]pyrimidine-6-carboxylic acid 3-methoxy-benzylamide;
3-[4-(N-Hydroxycarbamimidoyl)-benzyl]-1-methyl-2,4-dioxo-1,2,3,4-
tetrahydro-thieno[2,3-d]pyrimidine-6-carboxylic acid 4-methoxy-benzylamide;
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1-Methyl-2,4-dioxo-3-[4-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-
benzyl]-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-6-carboxylic acid 4-methoxy-
benzylamide;
l -Methyl-2,4-dioxo-3-[4-(5-thioxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-
benzyl]-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-6-carboxylic acid 4-methoxy-
benzylamide;
4-(5-Isopropyl-2H-pyrazol-3-yl)-pyridine;
3-Cyanomethyl-l -methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid 3-methoxy-benzylamide;
(E)-4-[6-(4-Methoxy-benzylcarbamoyl)-1-methyl-2,4-dioxo-l,4-dihydro-
2H-thieno[2,3-d]pyrimidin-3-yl]-but-2-enoic acid methyl ester;
(E)-4-[6-(4-Methoxy-benzylcarbamoyl)-1-methyl-2,4-dioxo-1,4-dihydro-
2H-thieno[2,3-d]pyrimidin-3-yl]-but-2-enoic acid;
3-(2-Benzenesulfonyl-ethyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-
thieno[2,3-d]pyrimidine-6-carboxylic acid 4-methoxy-benzylamide;
2-Methoxy-4-[6-(4-methoxy-benzylcarbamoyl)-l -methyl-2,4-dioxo-1,4-
dihydro-2H-thieno[2,3-d]pyrimidin-3-ylmethyl]-benzoic acid methyl ester;
3-(2-Methoxymethyl-1,1,3-trioxo-2,3-dihydro-1 H-1 l6-l ,2-benzisothiazol-
6-ylmethyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-6-
carboxylic acid 4-methoxy-benzylamide;
l -Methyl-3-oct-2-ynyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid 4-methoxy-benzylamide;
3-[2-(4-Chloro-benzenesulfonylamino)-ethyl]-1-methyl-2,4-dioxo-1,2,3,4-
tetrahydro-thieno[2,3-d]pyrimidine-6-carboxylic acid 4-methoxy-benzylamide;
3-[2-(4-Bromo-phenoxy)-ethyl]-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-
thieno[2,3-d]pyrimidine-6-carboxylic acid 4-methoxy-benzylamide;
3-[2-(4-Bromo-phenoxy)-ethyl]-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-
''thieno[2,3-d]pyrimidine-6-carboxylic acid 3-methoxy-benzylamide;
3-[2-(4-Fl uoro-phenox y)-ethyl ]-1-meth yl-2,4-dioxo-1,2,3,4-tetrahydro-
thieno[2,3-d]pyrimidine-6-carboxylic acid 4-methoxy-benzylamide;
3-[2-(4-Chloro-benzenesulfonyl)-ethyl]-1-methyl-2,4-dioxo-I,2,3,4-
tetrahydro-thieno[2,3-d]pyrimidine-6-carboxylic acid 4-methoxy-benzylamide;
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3-[2-(4-Fluoro-phenoxy)-ethyl]-1-methyl-2,4-dioxo-l ,2,3,4-tetrahydro-
thieno[2,3-d]pyrimidine-6-carboxylic acid 3-methoxy-benzylamide;
1-Methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-6-
carboxylic acid (2-methoxy-pyridin-4-ylmethyl)-amide;
3-Cyclohexylmethyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid 3-methoxy-benzylamide;
4-[6-(4-Methoxy-benzylcarbamoyl)-1-methyl-2,4-dioxo-1,4-dihydro-2H-
thieno[2,3-d]pyrimidin-3-ylmethyl]-2-methyl-benzoic acid methyl ester;
4-[6-(4-Methoxy-benzylcarbamoyl)-1-methyl-2,4-dioxo-1,4-dihydro-2H-
thieno[2,3-d]pyrimidin-3-ylmethyl]-benzoic acid methyl ester;
2-Methoxy-4-[6-(3-methoxy-benzylcarbamoyl)-1-methyl-2,4-dioxo-1,4-
dihydro-2H-thieno[2,3-d]pyrimidin-3-ylmethyl]-benzoic acid methyl ester;
4-[6-(3-Methoxy-benzylcarbamoyl)-1-methyl-2,4-dioxo-1,4-dihydro-2H-
thieno[2,3-d]pyrimidin-3-ylmethyl]-2-methyl-benzoic acid methyl ester;
I -Methyl-2,4-dioxo-3-(3-oxo-3-phenyl-propyl)-1,2,3,4-tetrahydro-
thieno[2,3-d]pyrimidine-6-carboxylic acid 4-methoxy-benzylamide;
3-[2-(4-Chloro-phenoxy)-ethyl]-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-
thieno[2,3-d]pyrimidine-6-carboxylic acid 3-methoxy-benzylamide;
l -Methyl-2,4-dioxo-3-[2-(3-trifluoromethyl-benzenesulfonyl)-ethyl]-
1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-6-carboxylic acid 3-methoxy-
benzylamide;
1-Methyl-2,4-dioxo-3-[2-(3-trifluoromethyl-benzenesulfonyl)-ethyl]-
1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-6-carboxylic acid 4-methoxy-
benzylamide;
3-[2-(4-Chloro-benzenesulfonyl)-ethyl]-1-methyl-2,4-dioxo-1,2,3,4-
tetrahydro-thieno[2,3-d]pyrimidine-6-carboxylic acid 3-methoxy-benzylamide;
and
3-(2-Amino-ethyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3
d]pyrimidine-6-carboxylic acid 4-methoxy-benzylamide; or a pharmaceutically
acceptable salt thereof.
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37. The combination according to Embodiment 23, wherein the compound of
Formula IB is selected from:
38. The combination according to Embodiment 23, wherein the compound of
Formula IB is selected from:
1-Methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-6-
carboxylic acid;
4-(6-Carbamoyl-l -methyl-2,4-dioxo-1,4-dihydro-2H-thieno[2,3-
d]pyrimidin-3-ylmethyl)-2-methyl-benzoic acid;
4-(6-Carbamoyl-1-methyl-2,4-dioxo-1,4-dihydro-2H-thieno[2,3-
d]pyrimidin-3-ylmethyl)-2-methyl-benzoic acid methyl ester;
4-[6-(3-Hydroxy-benzylcarbamoyl)-l -methyl-2,4-dioxo-1,4-dihydro-2H-
thieno[2,3-d]pyrimidin-3-ylmethyl]-2-methyl-benzoic acid;
4-(6-Carbamoyl-1-methyl-2,4-dioxo-1,4-dihydro-2H-thieno[2,3-
d]pyrimidin-3-ylmethyl)-2-hydroxy-benzoic acid;
3-(2-Amino-ethyl)-l -methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid 3-methoxy-benzylamide; and
4-(2,5-Di-pyridin-4-yl-thiophen-3-yl)-benzaldehyde.
39. The combination according to Embodiment 23, wherein the compound of
Formula IB is selected from:
1-Methyl-2,4-dioxo-3-( 1-phenyl-ethyl)-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid 4-methoxy-benzylamide;
1-Methyl-2,4-dioxo-3-(3-oxo-3-phenyl-propyl)-1,2,3,4-tetrahydro-
thieno[2,3-d]pyrimidine-6-carboxylic acid 4-methoxy-benzylamide;
3-((S)-3,7-Dimethyl-oct-6-enyl)-l -methyl-2,4-dioxo-1,2,3,4-tetrahydro-
thieno[2,3-d]pyrimidine-6-carboxylic acid 4-methoxy-benzylamide;
3-(2-Ethyl-hexyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid 4-methoxy-benzylamide;
3-(5-Cyano-pentyl)-l-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid 4-methoxy-benzylamide;
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3-(E)-But-2-enyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid 4-methoxy-benzylamide;
1-Methyl-3-(2-naphthalen-I -yl-ethyl)-2,4-dioxo-1,2,3,4-tetrahydro-
thieno[2,3-d]pyrimidine-6-carboxylic acid 4-methoxy-benzylamide;
1-Methyl-2,4-dioxo-3-(E)-pent-2-enyl-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid 4-methoxy-benzylamide;
1-Methyl-2,4-dioxo-3-(2-phenylsulfanyl-ethyl)-1,2,3,4-tetrahydro-
thieno[2,3-d]pyrimidine-6-carboxylic acid 4-methoxy-benzylamide;
3-sec-Butyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid 4-methoxy-benzylamide;
1-Methyl-3-(2-methyl-allyl)-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid 4-methoxy-benzylamide;
3-( 1-Ethyl-propyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid 4-methoxy-benzylamide;
1-Methyl-2,4-dioxo-3-pent-2-ynyl-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid 4-methoxy-benzylamide;
3-(2-Benzenesulfonyl-ethyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-
thieno[2,3-d]pyrimidine-6-carboxylic acid 4-methoxy-benzylamide;
I -Methyl-3-(3-methyl-but-2-enyl)-2,4-dioxo-1,2,3,4-tetrahydro-
thieno[2,3-d]pyrimidine-6-carboxylic acid 4-methoxy-benzylamide;
3-[2-(4-Fluoro-benzenesulfonyl)-ethyl]-l -methyl-2,4-dioxo-1,2,3,4-
tetrahydro-thieno[2,3-d]pyrimidine-6-carboxylic acid 4-methoxy-benzylamide;
1-Methyl-2,4-dioxo-3-[2-(toluene-4-sulfonyl)-ethyl]-l ,2,3,4-tetrahydro-
thieno[2,3-d]pyrimidine-6-carboxylic acid 4-methoxy-benzylamide;
3-[3-(4-Fluoro-phenyl)-3-oxo-propyl]-1-methyl-2,4-dioxo-1,2,3,4-
tetrahydro-thieno[2,3-d]pyrimidine-6-carboxylic acid 4-methoxy-benzylamide;
3-[3-(4-Chloro-phenyl)-3-oxo-propyl]-l -methyl-2,4-dioxo-7 ,2,3,4-
tetrahydro-thieno[2,3-d]pyrimidine-6-carboxylic acid 4-methoxy-benzylamide;
3-(2-Benzoylamino-ethyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-
thieno[2,3-d]pyrimidine-6-carboxylic acid 4-methoxy-benzylamide;
3-[2-(4-Bromo-phenoxy)-ethyl]-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-
thieno[2,3-d]pyrimidine-6-carboxylic acid 4-methoxy-benzylamide;
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3-Benzofurazan-5-ylmethyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-
thieno[2,3-d]pyrimidine-6-carboxylic acid 4-methoxy-benzylamide;
1-Methyl-2,4-dioxo-3-(2-phenoxy-ethyl)-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid 4-methoxy-benzylamide;
( 5-[6-(4-Methoxy-benzylcarbamoyl)-1-methyl-2,4-dioxo-I ,4-dihydro-2H-
thie,no[2,3-d]pyrimidin-3-ylmethyl]-isoxazol-3-yl }-carbamic acid methyl
ester;
3-Benzyloxycarbonylamino-5-[6-(4-methoxy-benzylcarbamoyl)-1-methyl-
2,4-dioxo-1,4-dihydro-2H-thieno[2,3-d]pyrimidin-3-yl]-4-oxo-pentanoic acid
tert-
butyl ester;
l0 3-[2-(4-Chloro-phenylsulfanyl)-ethyl]-1-methyl-2,4-dioxo-1,2,3,4-
tetrahydro-thieno[2,3-d]pyrimidine-6-carboxylic acid 3-methoxy-benzylamide;
1-Methyl-2,4-dioxo-3-( 1-phenyl-ethyl)-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid 3-methoxy-benzylamide;
1-Methyl-2,4-dioxo-3-(E)-pent-2-enyl-1,2,3,4-tetrahydro-thieno[2,3-
l5 d]pyrimidine-6-carboxylic acid 3-methoxy-benzylamide;
3-(2-Ethyl-hexyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid 3-methoxy-benzylamide;
1-Methyl-2,4-dioxo-3-(2-phenylmethanesulfonyl-ethyl)-1,2,3,4-
tetrahydro-thieno[2,3-d]pyrimidine-6-carboxylic acid 3-methoxy-benzylamide;
20 3-(5-Cyano-pentyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid 3-methoxy-benzylamide;
3-(E)-But-2-en yl-1-methyl-2,4-di ox o-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid 3-methoxy-benzylamide;
1-Methyl-3-(2-naphthalen-1-yl-ethyl)-2,4-dioxo-1,2,3,4-tetrahydro-
25 thieno[2,3-d]pyrimidine-6-carboxylic acid 3-methoxy-benzylamide;
1-Methyl-2,4-dioxo-3-(E)-pent-2-en yl-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid 3-methoxy-benzylamide;
1-Methyl-2,4-dioxo-3-(2-phenylsul fanyl-ethyl)-1,2,3,4-tetrahydro-
thieno[2,3-d]pyrimidine-6-carboxylic acid 3-methoxy-benzylamide;
30 3-sec-Butyl-l-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid 3-methoxy-benzylamide;
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1-Methyl-3-(2-methyl-allyl)-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid 3-methoxy-benzylamide;
3-( 1-Ethyl-propyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid 3-methoxy-benzylamide;
1-Methyl-2,4-dioxo-3-pent-2-ynyl-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid 3-methoxy-benzylamide;
1-Methyl-3-(3-methyl-but-2-enyl)-2,4-dioxo-1,2,3,4-tetrahydro-
thieno[2,3-d]pyrimidine-6-carboxylic acid 3-methoxy-benzylamide;
1-Methyl-2,4-dioxo-3-[2-(toluene-4-sulfonyl)-ethyl]-I ,2,3,4-tetrahydro-
thieno[2,3-d]pyrimidine-6-carboxylic acid 3-methoxy-benzylamide;
3-(2-Benzoylamino-ethyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-
thieno[2,3-d]pyrimidine-6-carboxylic acid 3-methoxy-benzylamide;
3-[2-(4-Bromo-phenoxy)-ethyl]-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-
thieno[2,3-d]pyrimidine-6-carboxylic acid 3-methoxy-benzylamide;
3-Benzofurazan-5-ylmethyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-
thieno[2,3-d]pyrimidine-6-carboxylic acid 3-methoxy-benzylamide;
1-Methyl-2,4-dioxo-3-(2-phenoxy-ethyl)-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid 3-methoxy-benzylamide;
{ 5-[6-(3-Methoxy-benzylcarbamoyl)-I -methyl-2,4-dioxo-1,4-dihydro-2H-
thieno[2,3-d]pyrimidin-3-ylmethyl]-isoxazol-3-yl }-carbamic acid methyl ester;
and
3-Benzyloxycarbonylamino-5-[6-(3-methoxy-benzylcarbamoyl)-1-methyl-
2,4-dioxo-1,4-dihydro-2H-thieno[2,3-d]pyrimidin-3-yl]-4-oxo-pentanoic acid
tert-
butyl ester.
40. The combination according to Embodiment 23, wherein the compound of
Formula IB is selected from:
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyri midine-
6-carboxylic acid methyl ester;
3-(4-Bromo-benzyl)-5-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid benzyl ester;
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3-(4-Fluoro-benzyl)-5-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid benzyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid pyridin-4-ylmethyl ester;
3-Benzyl-l -methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid benzo[b]thiophen-2-ylmethyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 1-methyl-1H-indol-5-ylmethyl ester;
3-Benzyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-6-
carboxylic acid thiophen-3-ylmethyl ester;
3-1,3-Benzodioxol-5-ylmethyl-1-methyl-2,4-dioxo-l ,2,3,4-tetrahydro-
thieno[2,3-d]pyrimidine-6-carboxylic acid benzyl ester;
1-Methyl-2,4-dioxo-3-pyridin-4-ylmethyl-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid benzyl ester;
' 3-(4-tert-Butyl-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid benzyl ester;
3-(3,4-Dichloro-benzyl)-5-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid benzyl ester;
1-Methyl-2,4-dioxo-3-(4-trifluoromethoxy-benzyl)-1,2,3,4-tetrahydro-
thieno[2,3-d]pyrimidine-6-carboxylic acid benzyl ester;
1-Methyl-3-naphthalen-2-ylmethyl-2,4-dioxo-1,2,3,4-tetrahydro-
thieno[2,3-d]pyrimidine-6-carboxylic acid benzyl ester;
3-(4-Cyano-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid benzyl ester;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid benzofuran-5-ylmethyl ester;
3-(3,S-Dimethoxy-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-
thieno[2,3-d]pyrimidine-6-carboxylic acid benzyl ester;
3-Benzyl-l -methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid benzyl ester;
3-(3,5-Dinitro-benzyl)-l -methyl-2,4-dioxo-l ,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid benzyl ester;
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3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid; and
3-(4-Carboxy-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid 2-ethoxy-benzyl ester.
41. The combination according to Embodiment 23, wherein the compound of
Formula IB is selected from:
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid [2-(3,4-dimethoxy-phenyl)-ethyl]-amide;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 4-amino-benzylamide;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid [2-(4-chloro-phenyl)-ethyl]-amide;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid (biphenyl-2-ylmethyl)-amide;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 3,4-dimethoxy-benzylamide;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid (2-pyridin-4-yl-ethyl)-amide;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 2-difluoromethoxy-benzylamide;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid [2-(3-ethoxy-phenyl)-ethyl]-amide;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 3-chloro-4-fluoro-benzylamide;
3-Benzyl-l -methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 2,4-dichloro-benzylamide;
3-Benzyl-l -methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid (2-phenyl-propyl)-amide;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 3,4,5-trimethoxy-benzylamide;
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3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 3-chloro-benzylamide;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 3,5-dimethoxy-benzylamide;
' 3-Benzyl-l-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 2,3-dimethoxy-benzylamide;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 3-trifluoromethyl-benzylamide;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 2-methoxy-benzylamide;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 2-methyl-benzylamide;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid (4-phenyl-butyl)-amide;
l5 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid (pyridin-3-ylmethyl)-amide;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 4-methoxy-benzylamide;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid ((S)-2,2-dimethyl-4-phenyl-1,3-dioxinan-5-yl)-amide;
3-Benzyl-l -methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid [2-(3-methoxy-phenyl)-ethyl]-amide;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 3-methoxy-benzylamide;
3-Benzyl-l-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid (thiophen-2-ylmethyl)-amide;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 2-chloro-benzylamide;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid (5-methyl-furan-2-ylmethyl)-amide;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid (2,2-Biphenyl-ethyl)-amide;
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3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid [2-(2-methoxy-phenyl)-ethyl]-amide;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid [2-(3-trifluoromethyl-phenyl)-ethyl]-amide;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 4-bromo-benzylamide;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid [2-(1H-indol-3-yl)-ethyl]-amide;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 3,5-dichloro-benzylamide;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid indan-1-ylamide;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid (furan-2-ylmethyl)-amide;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid [2-(4-methoxy-phenyl)-ethyl]-amide;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 2,4-dimethoxy-benzylamide;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 4-chloro-benzylamide;
3-Benzyl-I -methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid (1-phenyl-ethyl)-amide;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 3,4-dichloro-benzylamide;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 4-fluoro-3-trifluoromethyl-benzylamide;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid (2-pyridin-2-yl-ethyl)-amide;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid [2-(2,4-dimethyl-phenyl)-ethyl]-amide;
3-Benzyl-1-methyl-2,4-dioxo-I ,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid [2-(2,4-dichloro-phenyl)-ethyl]-amide;
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1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-6-
carboxylic acid 3-methoxy-benzylamide;
3-Cyanome'thyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid 4-methoxy-benzylamide;
' 3-Benzyl-l-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-
6-carboxylic acid 3-methoxy-benzylamide;
3-(4-Cyclopropylsulfamoyl-benzyl)-1-methyl-2,4-dioxo-1,2,3,4
tetrahydro-thieno[2,3-d]pyrimidine-6-carboxylic acid 3-methoxy-benzylamide;
1-Methyl-3-(6-vitro-pyridin-3-ylmethyl)-2,4-dioxo-1,2,3,4-tetrahydro-
thieno[2,3-d]pyrimidine-6-carboxylic acid 3-methoxy-benzylamide;
1-Methyl-3-(6-vitro-pyridin-3-ylmethyl)-2,4-dioxo-1,2,3,4-tetrahydro-
thieno[2,3-d]pyrimidine-6-carboxylic acid 4-methoxy-benzylamide;
I -Methyl-3-(6-vitro-pyridin-3-ylmethyl)-2,4-dioxo-1,2,3,4-tetrahydro-
thieno[2,3-d]pyrimidine-6-carboxylic acid (2-methoxy-pyridin-4-ylmethyl)-
amide;
3-Cyclohexylmethyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-
d]pyrimidine-6-carboxylic acid (2-methoxy-pyridin-4-ylmethyl)-amide;
3-{ 2-[( 1 H-Benzimidazole-5-carbonyl )-amino]-ethyl }-1-methyl-2,4-dioxo-
1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-6-carboxylic acid 3-methoxy-
benzylamide;
1-Methyl-2,4-dioxo-3-[2-(3-piperidin-1-yl-propionylamino)-ethyl]-1,2,3,4-
tetrahydro-thieno[2,3-d]pyrimidine-6-carboxylic acid 3-methoxy-benzylamide;
1-Methyl-2,4-dioxo-3-{ 2-[(6-pyrazol-1-yl-pyridine-3-carbonyl)-amino]-
ethyl}-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-6-carboxylic acid 3-methoxy-
benzylamide;
3-[2-(4-Diethylamino-benzoylamino)-ethyl]-1-methyl-2,4-dioxo-1,2,3,4-
tetrahydro-thieno[2,3-d]pyrimidine-6-carboxylic acid 3-methoxy-benzylamide;
3-{ 2-[(6-Chloro-pyridine-3-carbonyl)-amino]-ethyl }-1-methyl-2,4-dioxo-
1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-6-carboxylic acid 3-methoxy-
benzylamide;
l -Methyl-2,4-dioxo-3-{ 2-[( 1 H-pyrrole-2-carbonyl)-amino]-ethyl }-l ,2,3,4-
tetrahydro-thieno[2,3-d]pyrimidine-6-carboxylic acid 3-methoxy-benzylamide;
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3-[2-(2-Dimethylamino-acetylamino)-ethyl]-1-methyl-2,4-dioxo-1,2,3,4-
tetrahydro-thieno[2,3-d]pyrimidine-6-carboxylic acid 3-methoxy-benzylamide;
1-Methyl-2,4-dioxo-3- { 2-[(pyrazine-2-carbonyl)-amino]-ethyl }-1,2,3,4-
tetrahydro-thieno[2,3-d]pyrimidine-6-carboxylic acid 3-methoxy-benzylamide;
1-Methyl-3-[2-(2-methyl-2-methylamino-propionylamino)-ethyl]-2,4-
dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-6-carboxylic acid 3-methoxy-
benzylamide;
1-Methyl-2,4-dioxo-3-{ 2-[(pyrrolidine-2-carbonyl)-amino]-ethyl }-1,2,3,4-
tetrahydro-thieno[2,3-d]pyrimidine-6-carboxylic acid 3-methoxy-benzylamide;
1-Methyl-2,4-dioxo-3-{ 2-[3-(S-phenyl-1 H-pyrrol-2-yl)-propionylamino]-
ethyl}-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-6-carboxylic acid 3-methoxy-
benzylamide;.
l -Methyl-2,4-dioxo-3-{ 2-[2-(pyridin-4-ylsulfanyl)-acetylamino]-ethyl }-
1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-6-carboxylic acid 3-methoxy-
benzylamide;
3-(6-Amino-pyridin-3-ylmethyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-
thieno[2,3-d]pyrimidine-6-carboxylic acid 3-methoxy-benzylamide;
1-Methyl-2,4-dioxo-3-(3-phenyl-prop-2-ynyl)-1,2,3,4-tetrahydro-
thieno[2,3-d]pyrimidine-6-carboxylic acid 4-methoxy-benzylamide;
3-(6-Amino-pyridin-3-ylmethyl)-l-methyl-2,4-dioxo-1,2,3,4-tetrahydro-
thieno[2,3-d]pyrimidine-6-carboxylic acid 4-methoxy-benzylamide;
3-(6-Amino-pyridin-3-yl methyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-
thieno[2,3-d]pyrimidine-6-carboxylic acid (pyridin-4-ylmethyl)-amide;
l -Methyl-2,4-dioxo-3-[2-(pyridin-2-ylamino)-ethyl]-1,2,3,4-tetrahydro-
thieno[2,3-d]pyrimidine-6-carboxylic acid 4-methoxy-benzylamide;
l -Methyl-2,4-dioxo-3-[2-(pyrimidin-2-ylamino)-ethyl]-1,2,3,4-tetrahydro-
thieno[2,3-d]pyrimidine-6-carboxylic acid 4-methoxy-benzylamide; and
1-Methyl-2,4-dioxo-3-[2-(pyrimidin-2-ylamino)-ethyl]-1,2,3,4-tetrahydro-
thieno[2,3-d]pyrimidine-6-carboxylic acid 3-methoxy-benzylamide; or a
pharmaceutically acceptable salt thereof.
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42. A combination, comprising valdecoxib, or a pharmaceutically acceptable
salt thereof, and an allosteric carboxylic inhibitor of MMP-13 of Formula IC
R1
~W N W
X2
' A Z ~ ~ N\ IC
/ w
X3 ~ IZ3
Y O
or a pharmaceutically acceptable salt thereof, or an N-oxide thereof,
in which:
R~ represents a group selected from
~ hydrogen, amino,
~ (C~-C6)alkyl, (C3-C6)alkenyl, (C3-C6)alkynyl, mono(C~-C6)alkylamino(C~-
C6)alkyl, di(C~-C6)alkylamino(C~-C6)alkyl, aryl, aryl(C~-C6)alkyl,
heterocycle,
and 3- to 6-membered cycloalkyl(C~-C6)alkyl, these groups being unsubstituted
or
substituted with one or more groups, which may be identical or different,
selected
from amino, (C~-C6)alkyl, cyano, halo(C,-C6)alkyl, C(=O)OR4, OR4 and SR4, in
which R4 represents hydrogen or (C~-C6)alkyl,
W represents an oxygen atom, a sulphur atom, or a group =N-R', in which R'
represents (C~-C6)alkyl, hydroxyl, or cyano,
X1, X2 and X3 represent, independently of each other, a nitrogen atom or a
group -
C-R6 in which R6 represents a group selected from hydrogen, (C~-C6)alkyl,
amino,
mono(C~-C6)alkylamino, di(C~-C6)alkylamino, hydroxyl, (C~-C6)alkoxy, and
halogen,
with the proviso that not more than two of the groups X~, X2 and X3
simultaneously represent a nitrogen atom,
Y represents a group selected from oxygen atom, sulphur atom, -NH, and -N(C~-
C6)alkyl,
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Z represents:
~ an oxygen atom, a sulphur atom,
~ or a group -NR~ in which R~ represents a group selected from hydrogen,
(C,-C6)alkyl, aryl(C,-C6)alkyl, cycloalkyl, aryl, and heteroaryl, and
~ when Y is an oxygen atom, a sulphur atom, or a group -N(C,-C6)alkyl, Z
optionally represents a carbon atom which is unsubstituted or substituted with
a
(C~-C6)alkyl, an aryl, an aryl(C~-C6)alkyl, an aromatic or non-aromatic
heterocycle or a cycloalkyl,
n is an integer from 1 to 8 inclusive,
Zl represents -CR$R9 wherein R8 and R9, independently of each other, represent
a
group selected from hydrogen, (C~-C6)alkyl, halo(C~-C6)alkyl, halogen, amino,
OR4, SR4 or C(=O)OR4 in which R4 represents a hydrogen or (C~-C6)alkyl, and
~ when n is greater than or equal to 2, the hydrocarbon chain Z~ optionally
contains one or more multiple bonds,
~ and/or one of the carbon atoms in the hydrocarbon chain Z, may be
replaced with an oxygen atom, a sulphur atom which is unsubstituted or
substituted with one or two oxygen atoms, or a nitrogen atom which is
unsubstituted or substituted with a (C~-C6)alkyl,
~ and when one of the carbon atoms in the hydrocarbon chain Z~ is replaced
with a sulphur atom which is unsubstituted or substituted with one or two
oxygen
atoms, then the group-C(=Y)-Z- optionally may be absent in the general formula
(I),
A represents a group selected from
~ aromatic or non-aromatic, 5- or 6-membered monocycle comprising from 0
to 4 heteroatoms selected from nitrogen, oxygen and sulphur, and
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~ bicycle, composed of two aromatic or non-aromatic, 5- or 6-membered
rings, which may be identical or different, comprising from 0 to 4 heteroatoms
selected from nitrogen, oxygen and sulphur,
m is an integer from 0 to 7 inclusive,
the groups) R2, which may be identical or different, is (are) selected from
(C~-
C6)alkyl, halogen, -CN, NO2, SCF3, -CF3, -OCF3, -NR~oR> >, -OR~o, -SR~p, -
SOR,o, -S02R~o, -(CHz)kSOzNR~oRn, -Xs(CHZ)kC(=O)OR~o, -
(CH2)kC(=O)OR~o, -XS(CH2)~;C(=O)NR~oR»,
(CHZ)kC(=O)NR~pR> >, and -X4-R~2 in which:
~ XS represents a group selected from oxygen, sulphur optionally substituted
by one or two oxygen atoms, and nitrogen substituted by hydrogen or (C~-
C6)alkyl,
~ k is an integer from 0 to 3 inclusive,
~ R~o and R> >, which may be identical or different, are selected from
hydrogen and (C,-C6)alkyl,
~ X4 represents a group selected from single bond, -CHZ-, oxygen atom,
sulphur atom optionally substituted by one or two oxygen atoms, and nitrogen
atom substituted by hydrogen atom or (C~-C6)alkyl group,
~ R~2 represents an aromatic or non-aromatic, heterocyclic or non-
heterocyclic, 5- or 6-membered ring which is unsubstituted or substituted with
one
or more groups, which may be identical or different, selected from (C~-
C6)alkyl,
halogen, hydroxyl and amino, and when the ring is heterocyclic, it comprises
from
1 to 4 heteroatoms selected from nitrogen, oxygen and sulphur;
R3 represents a group selected from:
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hydrogen,
~ (C~-C6)alkyl, (C3-C6)alkenyl, (C3-C6)alkynyl, these groups being
unsubstituted or substituted with one or more groups, which may be identical
or
different, selected from amino, cyano, halo(C~-C6)alkyl, cycloalkyl, -
S C(=O)NR~oR», -C(=O)OR~o, OR,o, and SR~o, in which R~o and R», which may be
identical or different, represent hydrogen or (C~-C6)alkyl,
~ and the group of formula
(Rs) " (Z2 )/
9 P
in which p is an integer from 0 to 8 inclusive,
~ ZZ represents -CR~3R~4 wherein R~3 and R,4, independently of each other,
represent a group selected from hydrogen, (C~-C6)alkyl, phenyl, halo(C~-
C6)alkyl, halogen, amino, OR4, SR4 and -C(=O)OR4 in which R4 represents
hydrogen or (C~-C6)alkyl, and
when p is greater than or equal to 2, the hydrocarbon chain ZZ optionally
contains one or more multiple bonds,
~ and/or one of the carbon atoms in the hydrocarbon chain Z2 may be
replaced with an oxygen atom, a sulphur atom which is unsubstituted or
substituted with one or two oxygen atoms, a nitrogen atom which is
unsubstituted or substituted with a (C,-C6)alkyl, or a carbonyl group,
~ B represents a group selected from:
~ an aromatic or non-aromatic 5- or 6-membered monocycle comprising from
0 to 4 heteroatoms selected from nitrogen, oxygen and sulphur, and
~ a bicycle, composed of two aromatic or non-aromatic, 5- or 6-membered
rings, which may be identical or different, comprising from 0 to 4
heteroatoms selected from nitrogen, oxygen and sulphur,
q is an integer from 0 to 7 inclusive,
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the groups) R5, which may be identical or different, is (are) selected from
(C~-C6)alkyl, halogen, CN, NOZ, CF3, OCF3, -(CHZ)kNR~5R~6, -
N(R~s)C(=O)R~6, -N(R,s)C(=O)OR~6, -N(R,s)SOZR~6, -N(SOzR~s)2, -
' OR~s~ -S(O)k~R~s, -SOz-N(R~s)-(CH2)k2-NR~6Ra~ -
,(CH2)kS02NR~5R~6, -X~(CH2)kC(=O)OR~S, -
(CHZ)kC(=O)OR~S, -C(=O)O-(CH2),;2-NR~SR~6, -C(=O)O-(CH2)kz-C(=O)OR~B,
-XOCH2)kC(=O)NR~SR,6, -(CHz)kC(=O)NR~5R~6, -R~9-C(=O)OR~s, -X6-R2o,
and -C(=O)-R2~-NR~SR~6 in which
- X~ represents a group selected from oxygen atom, sulphur atom
optionally substituted by one or two oxygen atoms, and nitrogen atom
substituted by a hydrogen atom or a (C~-C6)alkyl group,
- k is an integer from 0 to 3 inclusive,
- kl is an integer from 0 to 2 inclusive,
- k2 is an integer from 1 to 4 inclusive,
- RCS, R,6 and R», which may be identical or different, are selected from
hydrogen and (C~-C6)alkyl,
- R~g represents a group selected from (C~-C6)alkyl, -R2~-NR,SR~6,
-Rz~-NR~S-C(=O)-R2,-NR~6R», and -C(=O)O-R2~-NR~5R~6 in which R2~
represents a linear or branched (C~-C6)alkylene group, and RCS, R~6 and R»
are as defined hereinbefore,
- R~9 represents a (C3-C6)cycloalkyl group,
- X6 represents a group selected from single bond, -CHZ-, oxygen atom,
sulphur atom optionally substituted by one or two oxygen atoms, and
nitrogen atom substituted by hydrogen atom or (C~-C6)alkyl group,
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- Rzo represents an aromatic or non-aromatic, heterocyclic or non-
heterocyclic, 5- or 6-membered ring, which is unsubstituted or substituted
with one or more groups, which may be identical or different, selected from
(C~-C6)alkyl, halogen, hydroxyl, oxo, cyano, tetrazole, amino, and -
C(=O)OR4 wherein R4 represents hydrogen or (C~-C6)alkyl, and, when the
ring is heterocyclic, it comprises from 1 to 4 heteroatoms selected from
nitrogen, oxygen and sulphur,
with the proviso that when X, represents a nitrogen atom, XZ cannot represent
a
carbon atom substituted with a methyl group or with NH-CH3.
43. The combination according to Embodiment 42, wherein the compound of
Formula IC is selected from:
4-[6-(4-Methox y-benzylcarbamoyl)-1-methyl-2,4-dioxo-1,4-dihydro-2H-
pyrido[3,4-d]pyrimidin-3-ylmethyl]-benzoic acid;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrido[3,4-d]pyrimidine-
6-carboxylic acid (1,3-benzodioxol-5-ylmethyl)-amide;
4-[6-(4-Fluoro-benzylcarbamoyl)-1-methyl-2,4-dioxo-l ,4-dihydro-2H-
quinazolin-3-ylmethyl]-benzoic acid;
1-Methyl-2,4-dioxo-3-[4-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-
benzyl]-1,2,3,4-tetrahydro-quinazoline-6-carboxylic acid 4-methoxy-
benzylamide;
4-[6-(4-Methoxy-benzylcarbamoyl)-1-methyl-2,4-dioxo-l ,4-dihydro-2H-
quinazolin-3-ylmethyl]-benzoic acid hemi calcium salt;
Methyl 4-[6-(4-Methoxy-benzylcarbamoyl )-1-methyl-2,4-dioxo-1,4-
dihydro-2H-pyrido[3,4-d]pyrimidin-3-ylmethyl]-benzoate;
4-[6-(3-Methoxy-benzylcarbamoyl)-1-methyl-2,4-dioxo-1,4-dihydro-2H -
quinazolin-3-ylmethyl]-benzoic acid;
1-Methyl-2,4-dioxo-3-[4-(2H-tetrazol-5-yl)-benzyl]-1,2,3,4-tetrahydro-
quinazoline-6-carboxylic acid 4-methoxy-benzylamide;
Methyl 2-hydroxy-4-[6-(4-methoxy-benzylcarbamoyl)-1-methyl-2,4-
dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl]-benzoate;
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3-(4-Chloro-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-
carboxylic acid 3-methoxy-benzylamide;
4-{ 6-[(1,3-Benzodioxol-5-ylmethyl)-carbamoyl]-1-methyl-2,4-dioxo-1,4-
dihydro-2H-quinazolin-3-ylmethyl }-benzoic acid;
' 2-Hydroxy-4-[6-(4-methoxy-benzylcarbamoyl)-1-methyl-2,4-dioxo-1,4-
dihydro-2H-quinazolin-3-ylmethyl]-benzoic acid;
Methyl 4-[6-(3-methoxy-benzylcarbamoyl)-1-methyl-2,4-dioxo-1,4-
dihydro-2H-quinazolin-3-ylmethyl]-benzoate;
3-(3-Fluoro-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quinazoline-6-
carboxylic acid 3-methoxy-benzylamide;
4-Pyridylmethyl 3-benzyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-
carboxylate;
Methyl 4-{ 6-[(1,3-benzodioxol-5-ylmethyl)-carbamoyl]-I -methyl-2,4-
di oxo- l ,4-dihydro-2H-qui nazol i n-3-yl methyl } -benzoate;
~ 1-Methyl-3-[4-(5-methyl-1,2,4-oxadiazol-3-yl)-benzyl]-2,4-dioxo-1,2,3,4-
tetrahydro-quinazoline-6-carboxylic acid 4-methoxy-benzylamide;
1-Methyl-3-[4-(3-methyl-1,2,4-oxadiazol-5-yl)-benzyl]-2,4-dioxo-1,2,3,4-
tetrahydro-quinazoline-6-carboxylic acid 4-methoxy-benzylamide;
3-(3-Fluoro-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quinazoline-6-
carboxylic acid (2-methoxy-pyridin-4-ylmethyl)-amide;
4-[6-(4-Methoxy-benzylcarbamoyl)-I -methyl-2,4-dioxo-1,4-dihydro-2H]-
quinazolin-3-ylmethyl]-benzoic acid;
1-{ 4-[6-(4-Methoxy-benzylcarbamoyl)-I -methyl-2,4-dioxo-1,4-dihydro-
2H-quinazolin-3-ylmethyl]-phenyl }-cyclopropanecarboxylic acid;
4-Pyridylmethyl 3-benzyl-l-methyl-2,4-dioxo-1,2,3,4-
tetrahydroquinazoline -6-carboxylate;
3-(4-Fluoro-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-
carboxylic acid 3-methoxy-benzylamide;
3-(3,4-Difluoro-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-
quinazoline-6-carboxylic acid 4-methoxy-benzylamide;
3-(4-Dimethylcarbamoyl-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-
tetrahydroquinazoline-6-carboxylic acid 4-methoxy-benzylamide;
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1-Methyl-3-[4-(2-methyl-2H-tetrazol-5-yl)-benzyl]-2,4-dioxo-1,2,3,4-
tetrahydro-quinazoline-6-carboxylic acid 4-methoxy-benzylamide;
3-(4-Bromo-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quinazoline-6-
carboxylic acid (2-methoxy-pyridin-4-ylmethyl)-amide;
3-(3,4-Difluoro-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-
quinazoline-6-carboxylic acid (pyridin-3-ylmethyl)-amide;
Benzo[ 1,3]dioxol-5-ylmethyl-3-benzyl-1-methyl-2,4-dioxo-1,2,3,4-
tetrahydroquinazoline-6-carboxylate;
3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic
acid (benzo[1,3]dioxol-5-ylmethyl)amide;
1-Methyl-3-(4-methylcarbamoyl-benzyl)-2,4-dioxo-1,2,3,4-tetrahydro-
quinazoline-6-carboxylic acid 4-methoxy-benzylamide;
3-(3-Fluoro-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quinazoline-6-
carboxylic acid 4-methoxy-benzylamide;
4-[6-(4-Hydroxy-benzylcarbamoyl)-1-methyl-2,4-dioxo-1,4-dihydro-2H-
quinazolin-3-ylmethyl]-benzoic acid;
Methyl 4-[6-(4-f7uoro-benzylcarbamoyl)-1-methyl-2,4-dioxo-1,4-dihydro-
2H-quinazolin-3-ylmethyl]-benzoate;
3-(4-Chlorobenzyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic
acid (benzo[1,3]dioxol-5-ylmethyl)amide;
1-Methyl-3-[4-( 1-methyl-1 H-tetrazol-5-yl)-benzyl]-2,4-dioxo-1,2,3,4-
tetrahydro-quinazoline-6-carboxylic acid 4-methoxy-benzylamide;
3-(4-Methoxybenzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-
carboxylic acid 4-methoxybenzylamide;
4-Pyridylmethyl 3-(benzo[1,3]dioxol-5-ylmethyl)-2,4-dioxo-1,2,3,4-
tetrahydroquinazoline-6-carboxylate;
Methyl 4-[6-(4-methoxy-benzylcarbamoyl)-1-methyl-2,4-dioxo-1,4-
dihydro-2H-quinazolin-3-ylmethyl]-benzoate;
1-Methyl-2,4-dioxo-3-pyridin-4-ylmethyl-l ,2,3,4-tetrahydro-quinazoline-
carboxylic acid 4-methoxy-benzylamide;
3-(4-Amino-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quinazoline-6-
carboxylic acid 4-methoxy-benzylamide;
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1-Methyl-3-(4-vitro-benzyl)-2,4-dioxo-1,2,3,4-tetrahydro-quinazoline-6-
carboxylic acid 4-methoxy-benzylamide;
2-Methoxy-4-[6-(4-methoxy-benzylcarbamoyl)-1-methyl-2,4-dioxo-1,4-
dihydro-2H-quinazolin-3-ylmethyl]-benzoic acid;
l -Methyl-3-(4-methylsulfamoyl-benzyl)-2,4-dioxo-1,2,3,4-tetrahydro-
quinazoline-6-carboxylic acid 4-methoxy-benzylamide;
1-Methyl-2,4-dioxo-3-(4-sulfamoyl-benzyl)-1,2,3,4-tetrahydro-
quinazoline-6-carboxylic acid 4-methoxy-benzylamide;
3-(4-Fluoro-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quinazoline-6-
carboxylic acid 4-methoxy-benzylamide;
3-(4-Fluoro-benzyl)-1-methyl-2,4-di oxo-1,2,3,4-tetrahydro-quinazol ine-6-
carboxylic acid (pyridin-4-ylmethyl)-amide;
3-(4-Methoxy-benzyl)-l -methyl-2,4-dioxo-1,2,3,4-tetrahydro-quinazoline-
6-carboxylic acid (pyridin-4-ylmethyl)-amide;
2-Methyl-4-[6-(4-methoxy-benzylcarbamoyl)-1-methyl-2,4-dioxo-1,4-
dihydro-2H-quinazolin-3-ylmethyl]-benzoic acid;
3-(4-Cyano-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quinazoline-6-
carboxylic acid 4-methoxy-benzylamide;
4-{ 1-Methyl-2,4-dioxo-6-[(pyridin-4-ylmethyl)-carbamoyl]-1,4-dihydro-
2H-quinazolin-3-ylmethyl}-benzoic acid;
3-(3-fluoro-4-methoxy-benzyl)-l -methyl-2,4-dioxo-1,2,3,4-tetrahydro-
quinazoline-6-carboxylic acid 4-methoxy benzylamine;
4-[ 1-Ethyl-6-(4-methoxy-benzylcarbamoyl)-2,4-dioxo-1,4-dihydro-2H-
quinazolin-3-ylmethyl]-benzoic acid;
3-(Benzo[1,3]dioxol-5-ylmethyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline
-6-carboxylic acid (benzo[1,3]dioxol-5-ylmethyl)amide;
3-(2'-Cyano-biphenyl-4-ylmethyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-
quinazoline-6-carboxylic acid 4-methoxy-benzylamide;
4-[ l -Methyl-6-(4-methylsulfanyl-benzylcarbamoyl)-2,4-dioxo-1,4-
dihydro-2H-quinazolin-3-ylmethyl]-benzoic acid;
4-{ 6-[(Benzofurazan-5-ylmethyl)-carbamoyl]-1-methyl-2,4-dioxo-1,4-
dihydro-2H-quinazolin-3-ylmethyl }-benzoic acid;
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Methyl 2-methyl-4-[6-(4-methoxy-benzylcarbamoyl)-I -methyl-2,4-dioxo-
1,4-dihydro-2H-quinazolin-3-ylmethyl]-benzoate;
3-(4-Acetyl amino-benzyl )-1-methyl-2,4-di oxo-1,2,3,4-tetrahydro-
quinazoline-6-carboxylic acid 4-methoxy-benzylamide;
3-(Benzo[1,3]dioxol-5-ylmethyl)-1-methyl-2,4-dioxo-1,2,3,4-
tetrahydroquinazoline-6-carboxylic acid (benzo[1,3]dioxol-5-ylmethyl)amide;
3-(4-Dimethylcarbamoylmethyl-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-
tetrahydro-quinazoline-6-carboxylic acid 4-methoxy-benzylamide;
Benzo[ 1,3]dioxol-5-ylmethyl 3-benzyl-2,4-dioxo-1,2,3,4-
tetrahydroquinazoline-6-carboxylate;
{ 4-[6-(4-Methoxy-benzylcarbamoyl)-1-methyl-2,4-dioxo-1,4-dihydro-2H-
quinazolin-3-ylmethyl]-phenyl }-acetic acid;
(4-{ 1-Methyl-2,4-dioxo-6-[(pyridin-4-ylmethyl)-carbamoyl]-l,4-dihydro-
2H-quinazolin-3-ylmethyl }-phenyl)-acetic acid;
3-Benzyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid
4-methoxybenzylamide;
Methyl {4-[6-(4-methoxy-benzylcarbamoyl)-1-methyl-2,4-dioxo-1,4-
dihydro-2H-quinazolin-3-ylmethyl]-phenyl }-acetate;
3-(3-Fluoro-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quinazoline-6-
carboxylic acid (pyridin-4-ylmethyl)-amide;
2,4-Dioxo-3-(thien-2-ylmethyl)-1,2,3,4-tetrahydroquinazoline-6-
carboxylic acid (benzo[1,3]dioxol-5-ylmethyl)amide;
l -Methyl-3-(4-methylsulfamoyl-benzyl)-2,4-dioxo-1,2,3,4-tetrahydro-
quinazoline-6-carboxylic acid 4-methoxy-benzylamide;
Methyl 4-{ 1-methyl-2,4-dioxo-6-[(pyridin-4-ylmethyl)-carbamoyl]-1,4-
dihydro-2H-quinazolin-3-ylmethyl }-benzoate;
2-Fluoro-4-[6-(4-methoxy-benzylcarbamoyl)-1-methyl-2,4-dioxo-1,4-
dihydro-2H-quinazolin-3-ylmethyl]-benzoic acid;
3-(4-Cyano-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrido[3,4-
d]pyrimidine-6-carboxylic acid 4-methoxy-benzylamide;
4-[6-(3-Methoxy-benzylcarbamoyl)-1-methyl-2,4-dioxo-1,4-dihydro-2H-
pyrido[3,4-d]pyrimidin-3-ylmethyl]-benzoic acid;
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4-[6-(4-Methoxy-benzylcarbamoyl)-1-methyl-2,4-dioxo-1,4-dihydro-2H-
quinazolin-3-ylmethyl]-benzoic acid hemi magnesium salt;
4-[6-(4-Methoxy-benzylcarbamoyl)-1-methyl-2,4-dioxo-1,4-dihydro-2H-
pyrido[2,3-d]pyrimidin-3-ylmethyl]-benzoic acid;
3-[4-(N-methylsulfonylamino)-benzyl]-1-methyl-2,4-dioxo-1,2,3,4-
tetrahydro-quinazoline-6-carboxylic acid 4-methoxy-benzylamide;
Ethyl 2-Fluoro-4-[6-(4-methoxy-benzylcarbamoyl)-1-methyl-2,4-dioxo-
1,4-dihydro-2H-quinazolin-3-ylmethyl]-benzoate;
3-(4-Dimethylsulfamoyl-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-
quinazoline-6-carboxylic acid 4-methoxy-benzylamide; and
3-(4-Methoxybenzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-
carboxylic acid (benzo[1,3]dioxol-5-ylmethyl)amide; or a pharmaceutically
acceptable salt thereof.
44: A combination, comprising valdecoxib, or a pharmaceutically acceptable
salt thereof, and an allosteric carboxylic inhibitor of MMP-13 of Formula
ID
w=X
\ N /N
z
N~ ID
(R4)m (Zl)n v ~ R3
Y O
or a pharmaceutically acceptable salt thereof, or an N-oxide thereof,
in which:
W represents N or C-R~; in which R~ is selected from:
~ hydrogen atom,
~ ORS, SRS in which RS is selected from hydrogen, (C~-C6)alkyl and aryl(C~-
C6)alkyl,
~ (C~-C6)alkyl, cycloalkyl of 3 to 8 carbon atoms optionally interrupted with
one
hetero atom selected from oxygen, sulfur and nitrogen, aryl, heteroaryl and
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aryl(C~-C6)alkyl, these groups being optionally substituted by (CHZ)p-OH or
(CH2)p-NH2 , in which p is an integer from 0 to 4 inclusive,
X represents N or C-R2 in which R2 is selected from:
~ hydrogen atom,
~ NR6R~, OR6, SR6 in which R6 and R~, identical or different, are selected
from
hydrogen, (C~-C6)alkyl and aryl(C~-C6)alkyl,
~ (C~-C6)alkyl, cycloalkyl of 3 to 8 carbon atoms optionally interrupted with
one
hetero atom selected from oxygen, sulfur and nitrogen, aryl, heteroaryl and
aryl(C~-C6)alkyl, these groups being optionally substituted by (CH2)p-OH or
(CHZ)p-NHZ , in which p is an integer from 0 to 4 inclusive,
Y represents a group selected from oxygen, sulfur, -NH, and -N(C~-C6)alkyl,
Z represents a group selected from:
~ oxygen, sulphur,
~ and -NR$ in which R8 represents a group selected from hydrogen, (C,-
C6)alkyl, aryl(C,-C6)alkyl, cycloalkyl, aryl, and heteroaryl, and
~ when Y is oxygen, sulphur, or -N(C~-C6)alkyl, Z optionally represents a
carbon atom which is optionally substituted by a group selected from (C~-
C6)alkyl, aryl, aryl(C~-C6)alkyl, aromatic heterocycle, non-aromatic
heterocycle,
and cycloalkyl,
n is an integer from 0 to 8 inclusive,
Z~ represents a group -CR9R~o wherein R9 and Rio, identical or different,
represent
a group selected from hydrogen, (C~-C6)alkyl, halo(C~-C6)alkyl, halogen,
NRSR»,
ORS, SRS and C(=O)ORS in which RS and R», identical or different, represents
hydrogen atom or (C~-C6)alkyl, and
~ when n is greater than or equal to 2, the hydrocarbon chain Z~ optionally
contains one or more multiple bonds,
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~ and/or one of the carbon atoms in the hydrocarbon chain Z~ may be replaced
with an oxygen atom, a sulphur atom which is optionally substituted by one or
two oxygen atoms, or a nitrogen atom which is optionally substituted by (C~-
C6)alkyl,
A represents a group selected from
~ aromatic or non-aromatic, 5- or 6-membered monocycle comprising from 0 to
4 heteroatoms selected from nitrogen, oxygen and sulphur, and
~ bicycle, composed of two aromatic or non-aromatic, 5- or 6-membered rings,
which may be identical or different, comprising from 0 to 4 heteroatoms
selected
70 from nitrogen, oxygen and sulphur,
m is an integer from 0 to 7 inclusive,
the'group(s) R4, which may be identical or different, is (are) selected from
(C~-
C6)alkyl, halogen, -CN, -NO2, -SCF3, -CF3, -OCF3, -NRSR> >, -ORS, -SRS, -SORS,
-SOZRS, -(CH2)kSOZNRSR> >, -XOCH2)kC(=O)ORS, -
(CH2)kC(=O)ORS, -X~ (CHZ)kC(=O)NRSR> >, -(CH2)kC(=O)NRSRt >, and -X2-
R~2 in which:
~ X~ represents a group selected from oxygen, sulphur optionally substituted
by
one or two oxygen atoms, and nitrogen substituted by hydrogen or (C~-C6)alkyl,
~ k is an integer from 0 to 3 inclusive,
~ RS and R», which may be identical or different, are selected from hydrogen
and (C~-C6)alkyl,
~ X2 represents a group selected from single bond, -CHZ-, oxygen atom, sulphur
atom optionally substituted by one or two oxygen atoms, and nitrogen atom
substituted by hydrogen atom or (C~-C6)alkyl group,
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~ R~z represents an aromatic or non-aromatic, heterocyclic or non-
heterocyclic,
5- or 6-membered ring which is optionally substituted by one or more groups,
which may be identical or different, selected from (C,-C6)alkyl, halogen,
hydroxyl, and amino, and when the ring is heterocyclic, it comprises from 1 to
4
heteroatoms selected from nitrogen, oxygen and sulphur,
R3 represents a group selected from:
~ hydrogen,
~ (C~-C6)alkyl, (CZ-C6)alkenyl, (C2-C6)alkynyl, these groups being optionally
substituted by one or more groups, which may be identical or different,
selected
from amino, cyano, halo(C,-C6)alkyl, cycloalkyl, -C(=O)NRSR», -C(=O)ORS, -
ORS, and -SRS, in which RS and R> >, which may be identical or different, are
as
defined hereinbefore,
~ and the group of formula
B
(Ri3) (
~~ in which p is an integer from 0 to 8 inclusive,
~~ ZZ represents -CR~4R~5 wherein R~4 and RCS, identical or different,
represent
a group selected from hydrogen, (C,-C6)alkyl, phenyl, halo(C~-C6)alkyl,
halogen, amino, -ORS, -NRSR~,, -SRS and -C(=O)OR5 in which RS and R»,
identical or different, are as defined hereinbefore, and
- when p is greater than or equal to 2, the hydrocarbon chain Z2 optionally
contains one or more multiple bonds,
- and/or one of the carbon atoms in the hydrocarbon chain ZZ may be
replaced with an oxygen atom, a sulphur atom which is optionally
substituted by one or two oxygen atoms, or a nitrogen atom which is
optionally substituted by (C,-C6)alkyl,
~~ B represents a group selected from:
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- aromatic or non-aromatic 5- or 6-membered monocycle comprising from 0
to 4 heteroatoms selected from nitrogen, oxygen and sulphur, and
- bicycle, composed of two aromatic or non-aromatic, 5- or 6-membered
rings, which may be identical or different, comprising from 0 to 4
' heteroatoms selected from nitrogen, oxygen and sulphur,
r q is an integer from 0 to 7 inclusive,
~~ the groups) R~3, which may be identical or different, is (are) selected
from
(C,-C6)alkyl, halogen, -CN, -NOz, -CF3, -OCF3, (C~-C6)acyl, -(CHz)kNR~6R»,
-Xs-(CHz)kNR~6R» -N(R~6)C(=O)Rm -N(R~6)C(=O)OR», -N(R~6)S02R»,
-N(SOZR~6)z~ -OR~6~ -S(O)k1R16, -(CHz)xSOzNR~6Rm~ -Xs(CHz)xC(=O)OR~6
-(CHz)xC(=O)OR~6, -X3(CHz)kC(=O)NR,6Rm -(CHz)kC(=O)NR~6Rn,
-C(=O)O-R,9-NR~6NR» and -X4-RIB, in which
= X3 represents a group selected from oxygen, sulphur optionally substituted
by one or two oxygen atoms, and nitrogen substituted by a hydrogen atom
or a (C~-C6)alkyl group,
- k is an integer from 0 to 3 inclusive,
- k~ is an integer from 0 to 2 inclusive,
- R~6 and R,~, which may be identical or different, are selected from
hydrogen and (C~-C6)alkyl,
- X4 represents a group selected from single bond, -CHz-, oxygen atom,
sulphur atom optionally substituted by one or two oxygen atoms, and
nitrogen atom substituted by hydrogen atom or (C,-C6)alkyl group,
- R~g represents an aromatic or non-aromatic, heterocyclic or non-
heterocyclic, 5- or 6-membered ring, which is optionally substituted by one
or more groups, which may be identical or different, selected from (C~-
C6)alkyl, halogen, hydroxyl, (Cl-C6)alkoxy, oxo, cyano,
tetrazole, -NRSR», and -C(=O)ORS wherein RS and R» are as defined
hereinbefore, and, when the ring is heterocyclic, it comprises from 1 to 4
heteroatoms selected from nitrogen, oxygen and sulphur,
R,9 represents a (C~-C6)alkylene group.
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45. The combination according to Embodiment 44, wherein the compound of
Formula m is selected from:
benzyl 4-benzyl-5-oxo-4H-[1,2,4]triazolo[4,3-a]quinazol-7-ylcarboxylate;
4-pyridylmethyl 4-benzyl-5-oxo-4H-[ 1,2,4]triazolo[4,3-a]quinazol-7-
ylcarboxylate;
N-(3,4-methylenedioxybenzyl)-4-benzyl-5-oxo-4H-[ 1,2,4]triazolo[4,3-
a]quinazol-7-ylcarboxamide;
N-(4-pyridylmethyl)-4-benzyl-5-oxo-4H-[ l ,2,4]triazolo[4,3-a]quinazol-7-
ylcarboxamide;
N-(3,4-methylenedioxybenzyl)-4-benzyl-5-oxo-4H-imidazo[ 1,2-
a]quinazol-7-ylcarboxamide;
N-(4-pyridylmethyl)-4-benzyl-5-oxo-4H-imidazo[1,2-a]quinazol-7-
ylcarboxamide;
N-(4-methoxybenzyl)-4-benzyl-5-oxo-4,5-dihydro[1,2,4]triazolo[4,3-
a]quinazoline-7-carboxamide;
N-[3-(4-pyridylsulphanyl)propyl]-4-benzyl-5-oxo-4,5-
dihydro[1,2,4]triazolo-[4,3-a] quinazoline-7-carboxamide;
N-(3,4-Methylenedioxybenzyl)-4-(4-cyanobenzyl)-5-oxo-4H-
[1,2,4]triazolo[4,3-a] quinazol-7-ylcarboxamide;
Methyl 4- { 7-[( 1,3-benzodioxol-5-ylmethyl)-carbamoyl]-5-oxo-SH-
[1,2,4]triazolo[4,3-a] quinazol-4-ylmethyl} benzoate;
Methyl 4-{ 7-[(4-methoxybenzyl)-carbamoyl]-5-oxo-SH-
[1,2,4]triazolo[4,3-a] quinazol-4-ylmethyl} benzoate;
Methyl 4-{7-[(pyridin-4-ylmethyl)-carbamoyl]-5-oxo-SH-
[1,2,4]triazolo[4,3-a] quinazol-4-ylmethyl} benzoate;
(2-Dimethylamino-ethyl) 4-[7-(4-fluoro-benzylcarbamoyl)-5-oxo-SH-
[1,2,4]triazolo[4,3-a] quinazol-4-ylmethyl] benzoate;
4-(4-Dimethylcarbamoyl-benzyl)-5-oxo-4,5-dihydro-[ 1,2,4]triazolo[4,3-
a]quinazoline-7-carboxylic acid 4-methoxy-benzylamide;
N-(pyridin-4ylmethyl)-4-(4-cyanobenzyl)-5-oxo-4H-[ l ,2,4]triazolo[4,3-
a]quinazol-7-ylcarboxamide;
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Methyl (4-{7-[(1,3-benzodioxol-5-ylmethyl)-carbamoyl]-5-oxo-SH-
[ 1,2,4]triazolo[4,3-a]quinazolin-4-ylmethyl } -phenyl)-acetate;
Methyl (4-{ 7-[(4-methoxy)-benzylcarbamoyl]-5-oxo-SH-
[1,2,4]triazolo[4,3-aJ quinazolin-4-ylmethyl }-phenyl)-acetate;
' Methyl (4-{7-[(pyridin-4-yl)-methylcarbamoyl]-5-oxo-SH-
[1,2,4]triazolo[4,3-a] quinazolin-4-ylmethyl}-phenyl)-acetate;
N-(pyridin-4-ylmethyl) 4-[3-(pyridin-4-yl)-2-propen-1-yl]-5-oxo-4H-
[1,2,4]triazolo[4,3-a] quinazol-7-ylcarboxamide;
4-[2-(4-Chloro-phenoxy)-ethyl]-5-oxo-4,5-dihydro-[ 1,2,4]triazolo[4,3-
a]quinazoline-7-carboxylic acid 4-methoxy-benzylamide;
4-{ 7-[(4-methoxybenzyl)-carbamoyl]-5-oxo-5H-[ 1,2,4]triazolo[4,3-
a]quinazol-4-ylmethyl } benzoic acid;
4-{ 7-[(1,3-benzodioxol-5-ylmethyl)-carbamoyl]-5-oxo-SH-
[1,2,4]triazolo[4,3-a]quinazol-4-ylmethyl} benzoic acid;
~ 4-{7-[(pyridin-4-ylmethyl)-carbamoyl]-5-oxo-SH-[1,2,4]triazolo[4,3-
a]quinazol-4-ylmethyl } benzoic acid;
4-{ 7-[(4-fluoro)-benzylcarbamoyl]-5-oxo-SH-[ 1,2,4]triazolo[4,3-
a]quinazol-4-ylmethyl } benzoic acid;
(4-{ 7-[(4-methoxy)-benzylcarbamoyl]-5-oxo-5H-[ 1,2,4]triazolo[4,3-
aJquinazolin-4-ylmethyl }-phenyl)-acetic acid;
(4-{ 7-[( 1,3-benzodioxol-5-ylmethyl)-carbamoyl]-5-oxo-SH-
[1,2,4]triazolo[4,3-a] quinazolin-4-ylmethyl}-phenyl)-acetic acid; and
(4-{ 7-[(pyridin-4-yl)-methylcarbamoyl]-5-oxo-5H-[ 1,2,4]triazolo[4,3-
a]quinazolin-4-ylmethyl }-phenyl)-acetic acid.
46. A combination, comprising valdecoxib, or a pharmaceutically acceptable
salt thereof, and an allosteric carboxylic inhibitor of MMP-l3 of Formula IE
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(O)n
1
O ~ S~Ni R
R3 X-C
N O
I2
R
or a pharmaceutically acceptable salt thereof, wherein:
nis0,l,or2;
X is O or NH;
R2 is H, Cl_C6 alkyl, or C1-C6 substituted alkyl;
R1 and R3 independently are H, acyl, substituted acyl, CI-C6 alkyl,
C1-C6 substituted alkyl, C2-C6 alkenyl, C2-C6 substituted alkenyl,
C2-C6 alkynyl, C~_C6 substituted alkynyl, (CH2)m aryl, (CHZ)m substituted
aryl,
(CH2)m heteroaryl, (CHZ)m substituted heteroaryl, (CH2)m cycloalkyl, or
(CH2)m substituted cycloalkyl; and
each m independently is an integer of from 0 to 6,
with the proviso that R3 is not (CH2)m biphenyl or (CH2)m substituted
biphenyl.
47. The combination according to Embodiment 46, wherein the compound of
Formula IE is a compound of Formula IIE
R3 O O~ ~O RI
wX ~ S:Ni
~ IIE
N- ' O
R2
or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, and X are
as
defined above for Embodiment 46.
48. The combination according to Embodiment 46, wherein the compound of
Formula IE is selected from:
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2-Benzyl-4-methyl-1, l ,3-trioxo-1,2,3,4-tetrahydro-
ll6-benzo[1,2,4]thiadiazine-7-carboxylic acid benzyl ester;
2-Benzyl-4-methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-
ll6-benzo[1,2,4]thiadiazine-7-carboxylic acid benzylamide;
2-Benzyl-4-methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-
ll6'benzo[1,2,4]thiadiazine-7-carboxylic acid (pyridin-4-ylmethyl)-amide;
2-Benzyl-4-methyl-l ,1,3-trioxo-1,2,3,4-tetrahydro-1 l6-
benzo[1,2,4]thiadiazine-7-carboxylic acid (lH-indol-5-ylmethyl)-amide;
2-Benzyl-4-methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1 l6-
benzo[1,2,4]thiadiazine-7-carboxylic acid 4-methoxy-benzylamide;
2-Benzyl-4-methyl-l ,1,3-trioxo-1,2,3,4-tetrahydro-I l6-
benzo[1,2,4]thiadiazine-7-carboxylic acid 4-(2-tert-butylsulfamoyl-ethyl)-
benzylamide;
2-Benzyl-4-methyl-1,1,3-tri oxo-1,2,3,4-tetrahydro-1 l6-
benzo[1,2,4]thiadiazine-7-carboxylic acid (IH-indol-2-ylmethyl)-amide;
2-Benzyl-4-methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1 l6-
benzo[1,2,4]thiadiazine-7-carboxylic acid 4-(2-sulfamoyl-ethyl)-benzylamide;
2-(4-Methanesulfonyl-benzyl)-4-methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-
ll6-benzo[1,2,4]thiadiazine-7-carboxylic acid benzylamide;
4-(7-Benzylcarbamoyl-4-methyl-1,1,3-trioxo-3,4-dihydro-1H-ll6-
benzo[1,2,4]thiadiazin-2-ylmethyl)-benzoic acid tert-butyl ester;
4-(7-Benzylcarbamoyl-4-methyl-1,1,3-trioxo-3,4-dihydro-1 H-1 l6-
benzo[1,2,4]thiadiazin-2-ylmethyl)-benzoic acid;
4-[7-(4-Methoxy-benzylcarbamoyl)-4-methyl-1,1,3-trioxo-3,4-dihydro-
1H-ll6-benzo[1,2,4]thiadiazin-2-ylmethyl]-benzoic acid tert-butyl ester;
4-[7-(4-Methoxy-benzylcarbamoyl)-4-methyl-1,1,3-trioxo-3,4-dihydro-
1H-ll6-benzo[1,2,4]thiadiazin-2-ylmethyl]-benzoic acid;
2-(4-Carbamoyl-benzyl)-4-methyl-I , I ,3-trioxo-I ,2,3,4-tetrahydro-1 l6-
benzo[1,2,4]thiadiazine-7-carboxylic acid 4-methoxy-benzylamide;
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2-(4-Methanesulfonyl-benzyl)-4-methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-
116-benzo[1,2,4]thiadiazine-7-carboxylic acid 4-methoxy-benzylamide;
2-Benzyl-4-methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1 l6-
benzo[1,2,4Jthiadiazine-7-carboxylic acid 4-fluoro-benzylamide;
4-Methyl-2-(4-nitro-benzyl)-1,1,3-trioxo-1,2,3,4-tetrahydro-1 l6-
benzo[1,2,4]thiadiazine-7-carboxylic acid 4-methoxy-benzylamide;
4-Methyl-2-(4-methylsulfamoyl-benzyl)-1,1,3-trioxo-1,2,3,4-tetrahydro-
Il6-benzo[1,2,4]thiadiazine-7-carboxylic acid 4-methoxy-benzylamide;
4-Methyl-2-[4-(morpholine-4-sulfonyl)-benzyl]-1,1,3-trioxo-1,2,3,4-
tetrahydro-ll6-benzo[1,2,4]thiadiazine-7-carboxylic acid 4-methoxy-
benzylamide;
4-[7-(4-Fluoro-benzylcarbamoyl)-4-methyl-1,1,3-trioxo-3,4-dihydro-1 H-
ll6-benzo[1,2,4]thiadiazin-2-ylmethyl]-benzoic acid methyl ester;
2-Benzyl-4-methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1 l6-
benzo[1,2,4Jthiadiazine-7-carboxylic acid (2-methoxy-pyridin-4-ylmethyl)-
amide;
4-Methyl-2-naphthalen-2-ylmethyl-1,1,3-trioxo-1,2,3,4-tetrahydro-ll6-
benzo[1,2,4]thiadiazine-7-carboxylic acid 4-methoxy-benzylamide;
2-Biphenyl-4-ylmethyl-4-methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1 l6-
benzo[1,2,4Jthiadiazine-7-carboxylic acid 4-methoxy-benzylamide;
2-Benzyl-4-methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1 l6-
benzo[1,2,4]thiadiazine-7-carboxylic acid (2,1,3-benzothiadiazol-5-ylmethyl)-
amide;
4-[7-(4-Fluoro-benzylcarbamoyl)-4-methyl-1,1,3-trioxo-3,4-dihydro-1 H-
Il6-benzo[1,2,4]thiadiazin-2-ylmethyl]-benzoic acid;
4-[7-(4-Methoxy-benzylcarbamoyl)-4-methyl-1,1,3-trioxo-3,4-dihydro-
lH-ll6-benzo[1,2,4]thiadiazin-2-ylmethylJ-benzoic acid 2-dimethylamino-ethyl
ester hydrochloride;
4-Methyl-1,1,3-trioxo-2-[4-(piperidi ne-1-carbonyl)-benzyl]-1,2,3,4-
tetrahydro-116-benzo[1,2,4]thiadiazine-7-carboxylic acid 4-methoxy-
benzylamide;
2-{4-[7-(4-Methoxy-benzylcarbamoyl)-4-methyl-1,1,3-trioxo-3,4-dihydro-
1H-ll6-benzo[1,2,4]thiadiazin-2-ylmethyl]-benzoylamino}-3-methyl-butyric acid;
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2-(4-Cyano-benzyl)-4-methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1 l6-
benzo[1,2,4]thiadiazine-7-carboxylic acid 4-methoxy-benzylamide;
{ 4-[7-(4-Methoxy-benzylcarbamoyl)-4-methyl-1,1,3-trioxo-3,4-dihydro-
1 H-1 ~,6-benzo[1,2,4]thiadiazin-2-ylmethyl]-phenyl }-acetic acid;
4-[7-(3-Methoxy-benzylcarbamoyl)-4-methyl-1,1,3-trioxo-3,4-dihydro-
1H-1~,6-benzo[1,2,4]thiadiazin-2-ylmethyl]-benzoic acid;
4-Methyl-1,1,3-trioxo-2-[4-(2H-tetrazol-5-yl)-benzyl]-1,2,3,4-tetrahydro-
1~,6-benzo[1,2,4]thiadiazine-7-carboxylic acid 4-methoxy-benzylamide;
2-(4-Amino-benzyl)-4-methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-17~6-
benzo[1,2,4]thiadiazine-7-carboxylic acid 4-methoxy-benzylamide;
2-Benzyl-4-methyl-1,1,3-trioxo-l ,2,3,4-tetrahydro-1 ~,6-
benzo[1,2,4]thiadiazine-7-carboxylic acid 3-methoxy-benzylamide;
4-Methyl-1,1,3-trioxo-2-pent-2-ynyl-1,2,3,4-tetrahydro-ll6-
bepzo[1,2,4]thiadiazine-7-carboxylic acid 4-methoxy-benzylamide;
4-Methyl-1,1,3-trioxo-2-(I-phenyl-ethyl)-1,2,3,4-tetrahydro-ll6-
benzo[1,2,4]thiadiazine-7-carboxylic acid 4-methoxy-benzylamide;
2-(5-Cyano-pentyl)-4-methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1 l6-
benzo[1,2,4]thiadiazine-7-carboxylic acid 4-methoxy-benzylamide;
2-(E)-But-2-enyl-4-methyl-1,1,3-trioxo-I ,2,3,4-tetrahydro-1 l6-
benzo[1,2,4]thiadiazine-7-carboxylic acid 4-methoxy-benzylamide;
4-Methyl-1,1,3-trioxo-2-(E)-pent-2-enyl-1,2,3,4-tetrahydro-1 l6-
benzo[1,2,4]thiadiazine-7-carboxylic acid 4-methoxy-benzylamide;
4-Methyl-2-(2-methyl-allyl)-1,1,3-trioxo-1,2,3,4-tetrahydro-1 l6-
benzo[1,2,4]thiadiazine-7-carboxylic acid 4-methoxy-benzylamide;
4-Methyl-2-(3-methyl-but-2-enyl)-1,1,3-trioxo-1,2,3,4-tetrahydro-ll6-
benzo[1,2,4]thiadiazine-7-carboxylic acid 4-methoxy-benzylamide;
4-Methyl-1, I ,3-trioxo-2-[2-(toluene-4-sulfonyl)-ethyl]-1,2,3,4-tetrahydro-
Il6-benzo[1,2,4]thiadiazine-7-carboxylic acid 4-methoxy-benzylamide;
2-[3-(4-Fluoro-phenyl)-3-oxo-propyl]-4-methyl-1,1,3-trioxo-I ,2,3,4-
tetrahydro-ll6-benzo[1,2,4]thiadiazine-7-carboxylic acid 4-methoxy-
benzylamide;
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4-Methyl-1,1,3-trioxo-2-{ 2-[( 1-phenyl-methanoyl)-amino]-ethyl }-1,2,3,4-
tetrahydro-ll6-benzo[1,2,4]thiadiazine-7-carboxylic acid 4-methoxy-
benzylamide;
2-Benzo[ 1,2,5]oxadiazol-5-yl methyl-4-methyl-1,1,3-trioxo-1,2,3,4-
tetrahydro-l l6-benzo[1,2,4]thiadiazine-7-carboxylic acid 4-methoxy-
benzylamide;
{5-[7-(4-Methoxy-benzylcarbamoyl)-4-methyl-1,1,3-trioxo-3,4-dihydro-
1H-ll6-benzo[1,2,4]thiadiazin-2-ylmethyl]-isoxazol-3-yl}-carbamic acid methyl
ester; and
4-Methyl-1,1,3-trioxo-2-thiazol-4-yl methyl-1,2,3,4-tetrahydro-1 l6-
benzo[1,2,4]thiadiazine-7-carboxylic acid 4-methoxy-benzylamide; or a
pharmaceutically acceptable salt thereof.
49. The combination according to Embodiment 46, wherein the compound of
Formula IE is selected from:
2-Benzyl-4-methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1 l6-
benzo[1,2,4]thiadiazine-7-carboxylic acid (pyridin-3-ylmethyl)-amide;
2-Benzyl-4-methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1 l6-
benzo[1,2,4]thiadiazine-7-carboxylic acid 4-methoxy-benzylamide;
2-Benzyl-4-methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1 l6-
benzo[1,2,4]thiadiazine-7-carboxylic acid 3-methoxy-benzylamide;
4-(7-Benzylcarbamoyl-4-methyl-1,1,3-trioxo-3,4-dihydro-1H-ll6-
benzo[1,2,4]thiadiazin-2-ylmethyl)-benzoic acid tert-butyl ester;
4-(4-Methyl-1,1,3-trioxo-7-[(pyridin-4-yl methyl)-carbamoyl]-3,4-dihydro-
1H-ll6-benzo[1,2,4]thiadiazin-2-ylmethyl)-benzoic acid tert-butyl ester;
4-(4-Methyl-1, l ,3-trioxo-7-[(pyridin-3-ylmethyl )-carbamoyl]-3,4-dihydro-
1H-ll6-benzo[1,2,4]thiadiazin-2-ylmethyl)-benzoic acid tert-butyl ester;
4-[7-(4-Methoxy-benzylcarbamoyl)-4-methyl-1, l ,3-trioxo-3,4-dihydro-
1H-ll6-benzo[1,2,4]thiadiazin-2-ylmethyl)-benzoic acid tert-butyl ester;
4-[7-(3-Methoxy-benzylcarbamoyl)-4-methyl-l ,1,3-trioxo-3,4-dihydro-
1H-ll6-benzo[1,2,4]thiadiazin-2-ylmethyl)-benzoic acid tert-butyl ester;
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4-(7-Benzylcarbamoyl-4-methyl-1,1,3-trioxo-3,4-dihydro-1 H-l l6-
benzo[1,2,4]thiadiazin-2-ylmethyl)-benzoic acid;
4-(4-Methyl-1,1,3-trioxo-7-[(pyridin-4-ylmethyl)-carbamoyl]-3,4-dihydro-
1H-ll6-benzo[1,2,4]thiadiazin-2-ylmethyl)-benzoic acid;
4-(4-Methyl-1,1,3-trioxo-7-[(pyridin-3-ylmethyl)-carbamoyl]-3,4-dihydro-
1H-ll6-benzo[1,2,4]thiadiazin-2-ylmethyl)-benzoic acid;
4-[7-(4-Methoxy-benzylcarbamoyl)-4-methyl-1,1,3-trioxo-3,4-dihydro-
lH-ll6-benzo[1,2,4]thiadiazin-2-ylmethyl)-benzoic acid;
4-[7-(3-Methox y-benzylcarbamoyl)-4-methyl-1,1,3-trioxo-3,4-dihydro-
1H-Il6-benzo[1,2,4]thiadiazin-2-ylmethyl)-benzoic acid;
{ 4-(7-Benzylcarbamoyl-4-methyl-1,1,3-trioxo-3,4-dihydro-1 H-1 l6-
benzo[1,2,4Jthiadiazin-2-ylmethyl)-phenyl}-acetic acid tert-butyl ester;
{ 4-(4-Methyl-1,1,3-trioxo-7-[(pyridin-4-ylmethyl)-carbamoyl]-3,4-
dihydro-1H-ll6-benzo[1,2,4Jthiadiazin-2-ylmethyl)-phenyl}-acetic acid tert-
butyl
ester;
{ 4-(4-Methyl-1,1,3-trioxo-7-[(pyridin-3-ylmethyl)-carbamoyl]-3,4-
dihydro-1H-ll6-benzo[1,2,4Jthiadiazin-2-ylmethyl)-phenyl}-acetic acid tert-
butyl
ester;
{ 4-[7-(4-Methoxy-benzylcarbamoyl)-4-methyl-1,1,3-trioxo-3,4-dihydro-
1H-ll6-benzo[1,2,4]thiadiazin-2-ylmethyl)-phenyl}-acetic acid tert-butyl
ester;
{ 4-[7-(3-Methoxy-benzylcarbamoyl)-4-methyl-1,1,3-trioxo-3,4-dihydro-
IH-ll6-benzo[1,2,4]thiadiazin-2-ylmethyl)-phenyl}-acetic acid tert-butyl
ester;
{ 4-(7-Benzylcarbamoyl-4-methyl-1,1,3-trioxo-3,4-dihydro-1 H-l l6-
benzo[1,2,4]thiadiazin-2-ylmethyl)-phenyl}-acetic acid;
{4-(4-Methyl-1,1,3-trioxo-7-[(pyridin-4-ylmethyl)-carbamoyl]-3,4-
dihydro-1H-l l6-benzo[1,2,4]thiadiazin-2-ylmethyl)-phenyl }-acetic acid;
{ 4-(4-Methyl-1,1,3-trioxo-7-[(pyridin-3-ylmethyl)-carbamoyl]-3,4-
dihydro-1H-ll6-benzo[1,2,4Jthiadiazin-2-ylmethyl)-phenyl}-acetic acid;
{ 4-[7-(4-Methoxy-benzylcarbamoyl)-4-methyl-1,1,3-trioxo-3,4-dihydro-
1H-ll6-benzo[1,2,4]thiadiazin-2-ylmethyl)-phenyl}-acetic acid;
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{ 4-[7-(3-Methoxy-benzylcarbamoyl)-4-methyl-1,1,3-trioxo-3,4-dihydro-
1H-ll6-benzo[1,2,4]thiadiazin-2-ylmethyl)-phenyl}-acetic acid;
2-(4-Methanesulfonyl-benzyl)-4-methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-
ll6-benzo[1,2,4]thiadiazine-7-carboxylic acid benzylamide;
2-(4-Methanesulfonyl-benzyl)-4-methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-
ll6-benzo[1,2,4]thiadiazine-7-carboxylic acid (pyridin-4-ylmethyl)-amide;
2-(4-Methanesulfonyl-benzyl)-4-methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-
ll6-benzo[1,2,4]thiadiazine-7-carboxylic acid (pyridin-3-ylmethyl)-amide;
2-(4-Methanesulfonyl-benzyl)-4-methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-
ll6-benzo[1,2,4]thiadiazine-7-carboxylic acid 4-methoxy-benzylamide;
2-(4-Methanesulfonyl-benzyl)-4-methyl-1, I ,3-trioxo-1,2,3,4-tetrahydro-
ll6-benzo[1,2,4]thiadiazine-7-carboxylic acid 3-methoxy-benzylamide;
4-Methyl-2-(4-methylsulfamoyl-benzyl)-1,1,3-trioxo-1,2,3,4-tetrahydro-
ll6-benzo[1,2,4]thiadiazine-7-carboxylic acid benzylamide;
4-Methyl-2-(4-methylsulfamoyl-benzyl)-1,1,3-trioxo-1,2,3,4-tetrahydro-
ll6-benzo[1,2,4]thiadiazine-7-carboxylic acid (pyridin-4-ylmethyl)-amide;
4-Methyl-2-(4-methylsulfamoyl-benzyl) -1,1,3-trioxo-1,2,3,4-tetrahydro-
ll6-benzo[1,2,4]thiadiazine-7-carboxylic acid (pyridin-3-ylmethyl)-amide;
4-Methyl-2-(4-methylsulfamoyl-benzyl) -1,1,3-trioxo-1,2,3,4-tetrahydro-
ll6-benzo[1,2,4]thiadiazine-7-carboxylic acid 4-methoxy-benzylamide;
4-Methyl-2-(4-methylsulfamoyl-benzyl) -1,1,3-trioxo-1,2,3,4-tetrahydro-
Il6-benzo[1,2,4]thiadiazine-7-carboxylic acid 3-methoxy-benzylamide;
2-(4-Dimethylsulfamoyl-benzyl)-4-methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-
ll6-benzo[1,2,4]thiadiazine-7-carboxylic acid benzylamide;
2-(4-Dimethylsulfamoyl-benzyl)-4-methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-
ll6-benzo[1,2,4]thiadiazine-7-carboxylic acid (pyridin-4-ylmethyl)-amide;
2-(4-Dimethylsulfamoyl-benzyl)-4-methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-
ll6-benzo[1,2,4]thiadiazine-7-carboxylic acid (pyridin-3-ylmethyl)-amide;
2-(4-Dimethylsulfamoyl-benzyl)-4-methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-
ll6-benzo[1,2,4]thiadiazine-7-carboxylic acid 4-methoxy-benzylamide;
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2-(4-Dimethylsulfamoyl-benzyl)-4-methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-
ll6-benzo[1,2,4]thiadiazine-7-carboxylic acid 3-methoxy-benzylamide;
2-Benzyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1 l6-benzo[ l ,2,4]thiadiazine-7-
carboxylic acid benzylamide;
2-Benzyl-1,1,3-trioxo-I ,2,3,4-tetrahydro-1 l6-benzo[ 1,2,4]thiadiazine-7-
carboxylic acid (pyridin-4-ylmethyl)-amide;
2-Benzyl-1, I ,3-trioxo-I ,2,3,4-tetrahydro-1 l6-benzo[ 1,2,4]thiadiazine-7-
carboxylic acid (pyridin-3-ylmethyl)-amide;
2-Benzyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1 l6-benzo[ 1,2,4]thiadiazine-7-
carboxylic acid 4-methoxy-benzylamide;
2-Benzyl-1, I ,3-trioxo-1,2,3,4-tetrahydro-1 l6-benzo[ 1,2,4]thiadiazine-7-
carboxylic acid 3-methoxy-benzylamide;
4-(7-Benzylcarbamoyl-I ,1,3-trioxo-3,4-dihydro-1 H-1 l6-
benzo[1,2,4]thiadiazin-2-ylmethyl)-benzoic acid tert-butyl ester;
4-(1,1,3-Trioxo-7-[(pyridin-4-ylmethyl)-carbamoyl]-3,4-dihydro-1H-Il6-
benzo[1,2,4]thiadiazin-2-ylmethyl)-benzoic acid tert-butyl ester;
4-(1,1,3-Trioxo-7-[(pyridin-3-ylmethyl)-carbamoyl]-3,4-dihydro-1 H-1 l6-
benzo[1,2,4]thiadiazin-2-ylmethyl)-benzoic acid tert-butyl ester;
4-[7-(4-Methoxy-benzylcarbamoyl)-1,1,3-trioxo-3,4-dihydro-1 H-1 l6-
benzo[1,2,4]thiadiazin-2-ylmethyl)-benzoic acid tent-butyl ester;
4-[7-(3-Methoxy-benzylcarbamoyl)-1,1,3-trioxo-3,4-dihydro-1 H-1 l6-
benzo[1,2,4]thiadiazin-2-ylmethyl)-benzoic acid tert-butyl ester;
4-(7-Benzylcarbamoyl-1, I ,3-trioxo-3,4-dihydro-1 H-1 l6-
benzo[1,2,4]thiadiazin-2-ylmethyl)-benzoic acid;
4-(1,1,3-Trioxo-7-[(pyridin-4-ylmethyl)-carbamoyl]-3,4-dihydro-IH-ll6-
benzo[1,2,4]thiadiazin-2-ylmethyl)-benzoic acid;
4-(1,1,3-Trioxo-7-[(pyridin-3-ylmethyl)-carbamoyl]-3,4-dihydro-1 H-1 l6-
benzo[1,2,4]thiadiazin-2-ylmethyl)-benzoic acid;
4-[7-(4-Methoxy-benzylcarbamoyl)-1,1,3-trioxo-3,4-dihydro-1 H-1 l6-
benzo[1,2,4]thiadiazin-2-ylmethyl)-benzoic acid;
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4-[7-(3-Methoxy-benzylcarbamoyl)-1,1,3-trioxo-3,4-dihydro-1 H-1 l6-
benzo[1,2,4]thiadiazin-2-ylmethyl)-benzoic acid;
{ 4-(7-Benzylcarbamoyl-1,1,3-trioxo-3,4-dihydro-1 H-1 l6-
benzo[1,2,4]thiadiazin-2-ylmethyl)-phenyl }-acetic acid tert-butyl ester;
{4-(1,1,3-Trioxo-7-[(pyridin-4-ylmethyl)-carbamoyl]-3,4-dihydro-1H-ll6-
benzo[1,2,4]thiadiazin-2-ylmethyl)-phenyl }-acetic acid tert-butyl ester;
{ 4-( 1,1,3-Trioxo-7-[(pyridin-3-ylmethyl)-carbamoyl]-3,4-dihydro-1 H-l l6-
benzo[1,2,4]thiadiazin-2-ylmethyl)-phenyl}-acetic acid tert-butyl ester;
{ 4-[7-(4-Methoxy-benzylcarbamoyl)-1,1,3-trioxo-3,4-dihydro-1 H-1 l6-
benzo[1,2,4]thiadiazin-2-ylmethyl)-phenyl}-acetic acid tert-butyl ester;
{ 4-[7-(3-Methoxy-benzylcarbamoyl)-1,1,3-trioxo-3,4-dihydro-1 H-1 l6-
benzo[1,2,4]thiadiazin-2-ylmethyl)-phenyl}-acetic acid tert-butyl ester;
{ 4-(7-Benzylcarbamoyl-1,1,3-trioxo-3,4-dihydro-1 H-l l6-.
benzo[1,2,4]thiadiazin-2-ylmethyl)-phenyl}-acetic acid;
{4-(1,1,3-Trioxo-7-[(pyridin-4-ylmethyl)-carbamoyl]-3,4-dihydro-1H-ll6-
benzo[1,2,4]thiadiazin-2-ylmethyl)-phenyl}-acetic acid;
{ 4-( 1,1,3-Trioxo-7-[(pyridin-3-ylmethyl)-carbamoyl]-3,4-dihydro-1 H-1 l6-
benzo[1,2,4]thiadiazin-2-ylmethyl)-phenyl}-acetic acid;
{ 4-[7-(4-Methoxy-benzylcarbamoyl) 1,1,3-trioxo-3,4-dihydro-1 H-1 l6-
benzo[1,2,4]thiadiazin-2-ylmethyl)-phenyl}-acetic acid;
{ 4-[7-(3-Methoxy-benzylcarbamoyl)-1,1,3-trioxo-3,4-dihydro-l H-l l6-
benzo[1,2,4]thiadiazin-2-ylmethyl)-phenyl}-acetic acid;
2-(4-Methanesulfonyl-benzyl)-l ,l ,3-trioxo-1,2,3,4-tetrahydro-1 l6-
benzo[1,2,4]thiadiazine-7-carboxylic acid benzylamide;
2-(4-Methanesulfonyl-benzyl)-1,1,3-trioxo-1,2,3,4-tetrahydro-ll6-
benzo[1,2,4]thiadiazine-7-carboxylic acid (pyridin-4-ylmethyl)-amide;
2-(4-Methanesulfonyl-benzyl)-1,1,3-trioxo-1,2,3,4-tetrahydro-1 l6-
benzo[1,2,4]thiadiazine-7-carboxylic acid (pyridin-3-ylmethyl)-amide;
2-(4-Methanesulfonyl-benzyl )- I , l ,3-trioxo-1,2,3,4-tetrahydro-1 l6-
benzo[1,2,4]thiadiazine-7-carboxylic acid 4-methoxy-benzylamide;
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2-(4-Methanesulfonyl-benzyl)-1,1,3-trioxo-1,2,3,4-tetrahydro-1 l6-
benzo[1,2,4]thiadiazine-7-carboxylic acid 3-methoxy-benzylamide;
2-(4-Methylsulfamoyl-benzyl)-1,1,3-trioxo-1,2,3,4-tetrahydro-1 l6-
benzo[1,2,4]thiadiazine-7-carboxylic acid benzylamide;
2-(4-Methylsulfamoyl-benzyl)-1,1,3-trioxo-1,2,3,4-tetrahydro-ll6-
berizo[1,2,4]thiadiazine-7-carboxylic acid (pyridin-4-ylmethyl)-amide;
2-(4-Methylsulfamoyl-benzyl) -1,1,3-trioxo-1,2,3,4-tetrahydro-ll6-
benzo[1,2,4]thiadiazine-7-carboxylic acid (pyridin-3-ylmethyl)-amide;
2-(4-Methylsulfamoyl-benzyl) -1,1,3-trioxo-1,2,3,4-tetrahydro-ll6-
benzo[1,2,4]thiadiazine-7-carboxylic acid 4-methoxy-benzylamide;
2-(4-Methylsulfamoyl-benzyl) -1,1,3-trioxo-1,2,3,4-tetrahydro-ll6-
benzo[1,2,4]thiadiazine-7-carboxylic acid 3-methoxy-benzylamide;
2-(4-Dimethylsulfamoyl-benzyl)-1,1,3-trioxo-1,2,3,4-tetrahydro-1 l6-
benzo[1,2,4]thiadiazine-7-carboxylic acid benzylamide;
2-(4-Dimethylsulfamoyl-benzyl)-1,1,3-trioxo-1,2,3,4-tetrahydro-ll6-
benzo[1,2,4]thiadiazine-7-carboxylic acid (pyridin-4-ylmethyl)-amide;
2-(4-Dimethylsulfamoyl-benzyl)-1,1,3-trioxo-1,2,3,4-tetrahydro-1 l6-
benzo[1,2,4]thiadiazine-7-carboxylic acid (pyridin-3-ylmethyl)-amide;
2-(4-Dimethylsulfamoyl-benzyl)-1, l ,3-trioxo-1,2,3,4-tetrahydro-1 l6-
benzo[1,2,4]thiadiazine-7-carboxylic acid 4-methoxy-benzylamide; and
2-(4-Dimethylsulfamoyl-benzyl)-1,1,3-trioxo-l ,2,3,4-tetrahydro-1 l6-
benzo[1,2,4]thiadiazine-7-carboxylic acid 3-methoxy-benzylamide; or a
pharmaceutically acceptable salt thereof.
50. A combination, comprising valdecoxib, or a pharmaceutically acceptable
salt thereof, and an allosteric carboxylic inhibitor of MMP-13 of Formula IF
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R2
N_ \ N
IF
B~C~C,A
II II
E E
or a pharmaceutically acceptable salt thereof,
wherein:
R2 is hydrogen, halo, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl,
C2-C6 alkynyl, N02, NR4R5, CN, or CF3;
E is independently O or S;
A and B independently are OR4 or NRSR6;
R4 and RS independently are H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl,
(CH.2)n aryl, (CH2)n cycloalkyl, (CH2)n heteroaryl, or R4 and RS when
taken together with the nitrogen to which they are attached complete a
3- to 8-membered ring, containing carbon atoms and optionally containing
a heteroatom selected from O, S, or NH, and optionally substituted or
unsubstituted; and
n is an integer from 0 to 6.
51. The combination according to Embodiment 50, wherein the compound of
Formula IF is a compound of Formula IIF
R2
N' \ N IIF
R40 ~ / OR4
O O
or a pharmaceutically acceptable salt thereof, wherein R2 is as defined above,
and
each R4 independently is as defined above for Embodiment 50.
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52. The combination according to Embodiment 50, wherein the compound of
Formula IF is a compound of Formula IIIF
R2
IIIF
R4R5 _N N-R4R5
or a pharmaceutically acceptable salt thereof, wherein R2 is as defined above,
and
each R4 and RS independently are as defined above for Embodiment 50.
53. The combination according to Embodiment 50, wherein the compound of
Formula IF is a compound of Formula IVF
R2
R6 ~
\N - 8
l0 N R IVF
(CH2)n-O ~ / O-(CH2)n ~
R
R O v O
or a pharmaceutically acceptable salt thereof, wherein n and R2 are as defined
above for Embodiment 50, and R6, R~, R8, and R9 independently are hydrogen,
halo, Cl-C6 alkyl, Cl-C6 alkoxy, vitro, or NH2.
54. The combination according to Embodiment 50, wherein the compound of
Formula 1F is a compound of Formula VF
R2
Ar -(CH2)n -N ~ / H -(CH2)n - Ar
O O VF
or a pharmaceutically acceptable salt thereof, wherein n and R2 are as defined
above for Embodiment 50, and each Ar independently is aryl or Het, wherein
aryl
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is phenyl or substituted phenyl, and Het is an unsubstituted or substituted
heteroaryl group.
55. The combination according to Embodiment 50, wherein the compound of
Formula IF is selected from:
Pyrimidine-4,6-dicarboxylic acid, (4-chloro-benzylamide), [(1,3-
benzodioxol-5-ylmethyl)-amide];
Pyrimidine-4,6-dicarboxylic acid, (4-carboxy-benzylamide), [(l,3-
benzodioxol-S-ylmethyl)-amide];
Pyrimidine-4,6-dicarboxylic acid, (4-carboxy-benzylamide), (4-methoxy-
benzylamide);
Pyrimidine-4,6-dicarboxylic acid, (4-carboxy-benzylamide), (3-methoxy-
benzylamide);
Pyrimidine-4,6-dicarboxylic acid, (4-carbomethoxy-benzylamide),
(3-methoxy-benzylamide);
Pyrimidine-4,6-dicarboxylic acid, (4-carboxy-benzylamide),
(3-pyridylmethylamide);
Pyrimidine-4,6-dicarboxylic acid, (4-carboxy-benzylamide),
(3-thiophenemethylamide);
Pyrimidine-4,6-dicarboxylic acid, (2,1,3-benzothiadiazol-5-ylmethyl)
amide, [(1,3-benzodioxol-5-ylmethyl)-amide];
Pyrimidine-4,6-dicarboxylic acid, (2,1,3-benzooxadiazol-5-ylmethyl)
amide, [(1,3-benzodioxol-S-ylmethyl)-amide];
Pyrimidine-4,6-dicarboxylic acid, (2,1,3-benzothiadiazol-5-ylmethyl)
amide, (4-methoxy-benzylamide);
Pyrimidine-4,6-dicarboxylic acid, (2,1,3-benzothiadiazol-5-ylmethyl)
amide, (3-methoxy-benzylamide);
Pyrimidine-4,6-dicarboxylic acid bis-(1,3-benzodioxol-5-ylmethyl) ester;
Pyrimidine-4,6-dicarboxylic acid, bis-(4-chloro-benzylamide);
Pyrimidine-4,6-dicarboxylic acid, bis-[(1,3-benzodioxol-5-ylmethyl)-
amide];
Pyrimidine-4,6-dicarboxylic acid, bis-(4-methoxy-benzylamide);
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Pyrimidine-4,6-dicarboxylic acid, bis-(3-methoxy-benzylamide);
Pyrimidine-4,6-dicarboxylic acid, bis-(4-carboxy-benzylamide); and
Pyrimidine-4,6-dicarboxylic acid, bis-(4-carbomethoxy-benzylamide); or a
pharmaceutically acceptable salt thereof.
56. , A combination, comprising valdecoxib, or a pharmaceutically acceptable
salt thereof, and an allosteric carboxylic inhibitor of MMP-13 of Formula IG
IG
B~ A
or a pharmaceutically acceptable salt thereof,
wherein:
R1 and R2 independently are hydrogen, halo, hydroxy, CI-C6 alkyl,
C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, N02, NR4R5, CN, or CF3;
E is independently O or S;
A and B independently are OR4 or NR4R5;
R4 and RS independently are H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl,
(CH2)n aryl, (CH2)n cycloalkyl, (CH2)n heteroaryl, or R4 and RS when
taken together with the nitrogen to which they are attached complete a
3- to 8-membered ring, containing carbon atoms and optionally containing
a heteroatom selected from O, S, or NH, and optionally substituted or
unsubstituted;
n is an integer from 0 to 6.
57. The combination according to Embodiment 56, wherein the compound of
Formula IG is a compound of Formula IIG
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R2
IIG
R4 OR4
or a pharmaceutically acceptable salt thereof, wherein Rl and R2 are as
defined
above, and each R4 independently is as defined above for Embodiment 56.
S 58. The combination according to Embodiment 56, wherein the compound of
Formula IG is a compound of Formula IIIG
R2
IIIG
R4R5-N -R4R5
or a pharmaceutically acceptable salt thereof, wherein RI and R2 are as
defined
above, and each R4 and RS independently are as defined above for
Embodiment 56.
59. The combination according to Embodiment 56, wherein the compound of
Formula IG is a compound of Formula IVG
R6 l
Rg IVG
(CH2)n-O O-(CH2)n ~
R R
or a pharmaceutically acceptable salt thereof, wherein n, RI, and R2 are as
defined above, and R6, R~, Rg, and R9 independently are hydrogen, halo,
Cl-C6 alkyl, CI-C6 alkoxy, vitro, or NH2.
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60. The combination according to Embodiment 56, wherein the compound of
Formula IG is a compound of Formula VG
Ar -(CH2)n -(CH2)n - Ar
O O VG
or a pharmaceutically acceptable salt thereof, wherein n, Rl, and R2 are as
defined above for Embodiment 56, and each Ar independently is aryl or
Het, wherein aryl is phenyl or substituted phenyl, and Het is an
unsubstituted or substituted heteroaryl group.
61. The combination according to Embodiment 56, wherein the compound of
Formula IG is selected from:
Pyridine-3,5-dicarboxylic acid, (4-chloro-benzylamide), [(1,3-
benzodioxol-5-ylmethyl)-amide];
Pyridine-3,5-dicarboxylic acid, (4-carboxy-benzylamide), [(1,3-
benzodioxol-5-ylmethyl)-amide];
Pyridine-3,5-dicarboxylic acid, (4-carboxy-benzylamide), (4-methoxy-
benzylamide);
Pyridine-3,5-dicarboxylic acid, (4-carboxy-benzylamide), (3-methoxy-
benzylamide);
Pyridine-3,5-dicarboxylic acid, (4-carbomethoxy-benzylamide), (3-
methoxy-benzylamide);
Pyridine-3,5-dicarboxylic acid, (4-carboxy-benzylamide), (3-
pyridylmethylamide);
Pyridine-3,5-dicarboxylic acid, (4-carboxy-benzylamide), (3-
thiophenemethyl amide);
Pyridine-3,5-dicarboxylic acid, (2,1,3-benzothiadiazol-5-ylmethyl) amide,
[( 1,3-benzodioxol-5-yl methyl)-amide];
Pyridine-3,5-dicarboxylic acid, (2,1,3-benzooxadiazol-5-ylmethyl) amide,
[(1,3-benzodioxol-5-ylmethyl)-amide];
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Pyridine-3,5-dicarboxylic acid, (2,1,3-benzothiadiazol-5-ylmethyl) amide,
(4-methoxy-benzylamide);
Pyridine-3,5-dicarboxylic acid, (2,1,3-benzothiadiazol-5-ylmethyl) amide,
(3-methoxy-benzylamide);
Pyridine-3,5-dicarboxylic acid bis-(1,3-benzodioxol-5-ylmethyl) ester;
2-Methoxy-pyridine-3,5-dicarboxylic acid bis-[(1,3-benzodioxol-5-
ylmethyl)-amide];
2-Ethoxy-pyridine-3,5-dicarboxylic acid bis-[(1,3-benzodioxol-5-
ylmethyl)-amide];
l0 2-Amino-pyridine-3,5-dicarboxylic acid bis-[(1,3-benzodioxol-5-
ylmethyl)-amide];
2-Oxo-1,2-dihydro-pyridine-3,5-dicarboxylic acid bis-benzylamide;
2-Methoxy-pyridine-3,5-dicarboxylic acid bis-benzylamide;
(3,5-Bis-benzylcarbamoyl-pyridin-2-yloxy)-acetic acid tert-butyl ester;
15 (3,5-Bis-benzylcarbamoyl-pyridin-2-yloxy)-acetic acid;
Pyridine-2,4-dicarboxylic acid bis-(3-methoxy-benzylamide);
Pyridine-2,4-dicarboxylic acid bis-[(1,3-benzodioxol-5-ylmethyl)-amide];
Pyridine-2,4-dicarboxylic acid bis-(2,4-dimethoxy-benzylamide);
Pyridine-2,4-dicarboxylic acid bis-(4-chloro-benzylamide);
20 Pyridine-2,4-dicarboxylic acid bis-benzylamide;
Pyridine-2,4-dicarboxylic acid bis-[(naphthalen-1-ylmethyl)-amide];
Pyridine-2,4-dicarboxylic acid bis-[(2-p-tolyl-ethyl)-amide];
Pyridine-2,4-dicarboxylic acid bis-(4-methoxy-benzylamide);
Pyridine-2,4-dicarboxylic acid bis-(3-fluoro-benzylamide);
25 Pyridine-2,4-dicarboxylic acid bis-(benzyl-ethyl-amide);
Pyridine-2,4-dicarboxylic acid bis-{ [2-(3,4-dimethoxy-phenyl)-ethyl]-
amide } ;
Pyridine-2,4-dicarboxylic acid bis-{ [2-(2-phenoxy-phenyl)-ethyl]-amide};
Pyridine-2,4-dicarboxylic acid bis-[(4-phenyl-butyl)-amide];
30 Pyridine-2,4-dicarboxylic acid bis-{ [2-(4-methoxy-phenyl)-ethyl]-amide};
Pyridine-2,4-dicarboxylic acid bis-{ [2-(2-fluoro-phenyl)-ethyl]-amide};
Pyridine-2,4-dicarboxylic acid bis-{[2-(3-chloro-phenyl)-ethyl]-amide};
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Pyridine-2,4-dicarboxylic acid bis-{ [2-(2,4-dimethyl-phenyl)-ethyl]-
amide } ;
Pyridine-2,4-dicarboxylic acid bis-[(2-o-tolyl-ethyl)-amide];
Pyridine-2,4-dicarboxylic acid bis-{[2-(4-ethyl-phenyl)-ethyl]-amide};
' Pyridine-2,4-dicarboxylic acid bis-[(2-phenyl-propyl)-amide];
Pyridine-2,4-dicarboxylic acid bis-[(1,2-diphenyl-ethyl)-amide];
Pyridine-2,4-dicarboxylic acid bis-(2,4-dichloro-benzylamide);
Pyridine-2,4-dicarboxylic acid bis-[(biphenyl-2-ylmethyl)-amide];
Pyridine-2,4-dicarboxylic acid bis-(3,4,5-trimethoxy-benzylamide);
Pyridine-2,4-dicarboxylic acid bis-(3-chloro-benzylamide);
Pyridine-2,4-dicarboxylic acid bis-(3,5-dimethoxy-benzylamide);
Pyridine-2,4-dicarboxylic acid bis-(3,4-dimethoxy-benzylamide);
Pyridine-2,4-dicarboxylic acid bis-(ethyl-pyridin-4-ylmethyl-amide);
Pyridine-2,4-dicarboxylic acid bis-[(2-pyridin-4-yl-ethyl)-amide];
S Pyridine-2,4-dicarboxylic acid bis-[(2-pyridin-3-yl-ethyl)-amide];
Pyridine-2,4-dicarboxylic acid bis-{[2-(4-chloro-phenyl)-ethyl]-amide};
Pyridine-2,4-dicarboxylic acid bis-[(pyridin-4-ylmethyl)-amide];
Pyridine-2,4-dicarboxylic acid bis-(3,5-bis-trifluoromethyl-benzylamide);
Pyridine-2,4-dicarboxylic acid bis-(2,3-dimethoxy-benzylamide);
Pyridine-2,4-dicarboxylic acid bis-(3-trifluoromethyl-benzylamide);
Pyridine-2,4-dicarboxylic acid bis-(2-trifluoromethoxy-benzylamide);
Pyridine-2,4-dicarboxylic acid bis-(3-difluoromethoxy-benzylamide);
Pyridine-2,4-dicarboxylic acid bis-(2-difluoromethoxy-benzylamide);
Pyridine-2,4-dicarboxylic acid bis-(4-fluoro-3-trifluoromethyl-
benzylamide);
Pyridine-2,4-dicarboxylic acid bis-(2-methoxy-benzylamide);
Pyridine-2,4-dicarboxylic acid bis-{[2-(3-ethoxy-phenyl)-ethyl]-amide};
Pyridine-2,4-dicarboxylic acid bis-(3-chloro-4-fluoro-benzylamide);
Pyridine-2,4-dicarboxylic acid bis-(2,4-difluoro-benzylamide);
Pyridine-2,4-dicarboxylic acid bis-(4-amino-benzylamide);
Pyridine-2,4-dicarboxylic acid bis-(2-methyl-benzylamide);
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Pyridine-2,4-dicarboxylic acid bis-{ [bis-(4-methoxy-phenyl)-methyl]-
amide } ;
Pyridine-2,4-dicarboxylic acid bis-[(3,3-diphenyl-propyl)-amide];
Pyridine-2,4-dicarboxylic acid bis-[(1-methyl-3-phenyl-propyl)-amide];
Pyridine-2,4-dicarboxylic acid bis-[(3,4-dimethoxy-phenyl)-amide];
Pyridine-2,4-dicarboxylic acid bis-(2-fluoro-benzylamide);
Pyridine-2,4-dicarboxylic acid bis-[(3-imidazol-1-yl-propyl)-amide];
Pyridine-2,4-dicarboxylic acid bis-(2-chloro-benzylamide);
Pyridine-2,4-dicarboxylic acid bis-(2-trifluoromethyl-benzylamide);
Pyridine-2,4-dicarboxylic acid bis-(4-methyl-benzylamide);
Pyridine-2,4-dicarboxylic acid bis-{[2-(3-methoxy-phenyl)-ethyl]-amide};
Pyridine-2,4-dicarboxylic acid bis-[(l-phenyl-ethyl)-amide];
Pyridine-2,4-dicarboxylic acid bis-[(pyridin-3-ylmethyl)-amide];
Pyridine-2,4-dicarboxylic acid bis-[(4-ethoxy-phenyl)-amide];
Pyridine-2,4-dicarboxylic acid bis-(phenethyl-amide);
Pyridine-2,4-dicarboxylic acid bis-[(thiophen-2-ylmethyl)-amide];
Pyridine-2,4-dicarboxylic acid bis-(4-trifluoromethyl-benzylamide);
Pyridine-2,4-dicarboxylic acid bis-[(5-methyl-furan-2-ylmethyl)-amide];
Pyridine-2,4-dicarboxylic acid bis-{[1-(4-fluoro-phenyl)-ethyl]-amide};
Pyridine-2,4-dicarboxylic acid bis-(2-amino-benzylamide);
Pyridine-2,4-dicarboxylic acid bis-[(1-naphthalen-1-yl-ethyl)-amide];
Pyridine-2,4-dicarboxylic acid bis-{ [2-(4-hydroxy-phenyl)-ethyl]-amide};
Pyridine-2,4-dicarboxylic acid bis-(3-trifluoromethoxy-benzylamide);
Pyridine-2,4-dicarboxylic acid bis-{[1-(3-methoxy-phenyl)-ethyl]-amide};
Pyridine-2,4-dicarboxylic acid bis-[(1-phenyl-propyl)-amide];
Pyridine-2,4-dicarboxylic acid bis-{ [2-(2-methoxy-phenyl)-ethyl]-amide};
Pyridine-2,4-dicarboxylic acid bis-{ [2-(3-trifluoromethyl-phenyl)-ethyl]-
amide } ;
Pyridine-2,4-dicarboxylic acid bis-indan-1-ylamide;
Pyridine-2,4-dicarboxylic acid bis-indan-1-ylamide;
Pyridine-2,4-dicarboxylic acid bis-(3,4-dichloro-benzylamide);
Pyridine-2,4-dicarboxylic acid bis-[(2-ethoxy-ethyl)-amide];
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Pyridine-2,4-dicarboxylic acid bis-{ [2-(4-bromo-phenyl)-ethyl]-amide};
Pyridine-2,4-dicarboxylic acid bis-[(2-pyridin-2-yl-ethyl)-amide];
Pyridine-2,4-dicarboxylic acid bis-[(2-thiophen-2-yl-ethyl)-amide];
Pyridine-2,4-dicarboxylic acid bis-{ [2-(5-methoxy-1 H-indol-3-yl)-ethyl]-
amide);
Pyridine-2,4-dicarboxylic acid bis-{[2-(1H-indol-3-yl)-ethyl]-amide}; and
Pyridine-2,4-dicarboxylic acid bis-(3,5-dichloro-benzylamide); or a
pharmaceutically acceptable salt thereof.
62. A pharmaceutical composition, comprising a combination of valdecoxib,
or a pharmaceutically acceptable salt thereof, and an allosteric carboxylic
inhibitor
of MMP-13, or a pharmaceutically acceptable salt thereof, and a
pharmaceutically
acceptable carrier, diluent, or excipient.
63.' The pharmaceutical composition according to Embodiment 62, wherein
the combination is the combination according to any one of Embodiments 1 to
61.
64. The pharmaceutical composition according to Embodiment 62 or 63,
wherein valdecoxib, or the pharmaceutically acceptable salt thereof, is in
unit
dosage form in an amount of from 1 milligram to 50 milligrams, and the
allosteric
carboxylic inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof,
is
in unit dosage form in an amount of from l0 milligrams to 600 milligrams.
65. The pharmaceutical composition according to Embodiment 64, wherein
valdecoxib, or the pharmaceutically acceptable salt thereof, is in unit dosage
form
in an amount of from 5 milligrams to 50 milligrams, and the allosteric
carboxylic
inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof, is in unit
dosage form in an amount of from 10 milligrams to 300 milligrams.
66. The pharmaceutical composition according to Embodiment 65, wherein
valdecoxib, or the pharmaceutically acceptable salt thereof, is in unit dosage
form
in an amount of from 5 milligrams to 25 milligrams, and the allosteric
carboxylic
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inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof, is in unit
dosage form in an amount of from 25 milligrams to 300 milligrams.
67. The pharmaceutical composition according to Embodiment 66, wherein
valdecoxib, or the pharmaceutically acceptable salt thereof, is in unit dosage
form
in an amount of from 5 milligrams to 25 milligrams, and the allosteric
carboxylic
inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof, is in unit
dosage form in an amount of from 25 milligrams to 200 milligrams.
68. The pharmaceutical composition according to Embodiment 67, wherein
valdecoxib, or the pharmaceutically acceptable salt thereof, is in unit dosage
form
in an amount of from 1 milligram to 5 milligrams, and the allosteric
carboxylic
inhibitor .of MMP-13, or a pharmaceutically acceptable salt thereof, is in
unit
dosage form in an amount of from 25 milligrams to 100 milligrams.
69. A method of treating cartilage damage in a mammal in need thereof,
comprising administering to the mammal a therapeutically effective amount of a
combination comprising valdecoxib, or a pharmaceutically acceptable salt
thereof,
and an allosteric carboxylic inhibitor of MMP-13, or a pharmaceutically
acceptable salt thereof.
70. The method according to Embodiment 69, wherein the combination is the
combination according to any one of Embodiments 1 to 61.
71. A method of treating cartilage damage in a mammal in need thereof,
comprising administering to the mammal a therapeutically effective amount of a
pharmaceutical composition, comprising a combination of valdecoxib, or a
pharmaceutically acceptable salt thereof, and an allosteric carboxylic
inhibitor of
MMP-13, or a pharmaceutically acceptable salt thereof, and a pharmaceutically
acceptable carrier, diluent, or excipient.
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72. The method according to Embodiment 71, wherein the combination is the
combination according to any one of Embodiments 1 to 61.
73. The method according to Embodiment 71 or 72, wherein valdecoxib, or
the pharmaceutically acceptable salt thereof, is in unit dosage form in an
amount
of from 1 milligram to 50 milligrams, and the allosteric carboxylic inhibitor
of
MMP-13, or a pharmaceutically acceptable salt thereof, is in unit dosage form
in
an amount of from 10 milligrams to 600 milligrams.
74. The method according to Embodiment 73, wherein valdecoxib, or the
pharmaceutically acceptable salt thereof, is in unit dosage form in an amount
of
from 5 milligrams to 50 milligrams, and the allosteric carboxylic inhibitor of
MMP-13, or a pharmaceutically acceptable salt thereof, is in unit dosage form
in
an amount of from 10 milligrams to 300 milligrams.
75. The method according to Embodiment 74, wherein valdecoxib, or the
pharmaceutically acceptable salt thereof, is in unit dosage form in an amount
of
from 5 milligrams to 25 milligrams, and the allosteric carboxylic inhibitor of
MMP-13, or a pharmaceutically acceptable salt thereof, is in unit dosage form
in
an amount of from 25 milligrams to 300 milligrams.
76. The method according to Embodiment 75, wherein valdecoxib, or the
pharmaceutically acceptable salt thereof, is in unit dosage form in an amount
of
from 5 milligrams to 25 milligrams, and the allosteric carboxylic inhibitor of
MMP-13, or a pharmaceutically acceptable salt thereof, is in unit dosage form
in
an amount of from 25 milligrams to 200 milligrams.
77. The method according to Embodiment 76, wherein valdecoxib, or the
pharmaceutically acceptable salt thereof, is in unit dosage form in an amount
of
from 1 milligram to 5 milligrams, and the allosteric carboxylic inhibitor of
MMP-
13, or a pharmaceutically acceptable salt thereof, is in unit dosage form in
an
amount of from 25 milligrams to 100 milligrams.
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78. A method of treating inflammation in a mammal in need thereof,
comprising administering to the mammal a therapeutically effective amount of a
combination comprising valdecoxib, or a pharmaceutically acceptable salt
thereof,
and an allosteric carboxylic inhibitor of MMP-13, or a pharmaceutically
acceptable salt thereof.
79. The method according to Embodiment 78, wherein the combination is the
combination according to any one of Embodiments 1 to 61.
80. A method of treating inflammation in a mammal in need thereof,
comprising administering to the mammal a therapeutically effective amount of a
pharmaceutical composition, comprising a combination of valdecoxib, or a
pharmaceutically acceptable salt thereof, and an allosteric carboxylic
inhibitor of
MMP-13, or a pharmaceutically acceptable salt thereof, and a pharmaceutically
acceptable carrier, diluent, or excipient.
81. The method according to Embodiment 80, wherein the combination is the
combination according to any one of Embodiments 1 to 61.
82. The method according to Embodiment 80 or 81, wherein valdecoxib, or
the pharmaceutically acceptable salt thereof, is in unit dosage form in an
amount
of from 1 milligram to 50 milligrams, and the allosteric carboxylic inhibitor
of
MMP-13, or a pharmaceutically acceptable salt thereof, is in unit dosage form
in
an amount of from 10 milligrams to 600 milligrams.
83. The method according to Embodiment 82, wherein valdecoxib, or the
pharmaceutically acceptable salt thereof, is in unit dosage form in an amount
of
from 5 milligrams to 50 milligrams, and the allosteric carboxylic inhibitor of
MMP-13, or a pharmaceutically acceptable salt thereof, is in unit dosage form
in
an amount of from 10 milligrams to 300 milligrams.
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84. The method according to Embodiment 83, wherein valdecoxib, or the
pharmaceutically acceptable salt thereof, is in unit dosage form in an amount
of
from 5 milligrams to 25 milligrams, and the allosteric carboxylic inhibitor of
MMP-13, or a pharmaceutically acceptable salt thereof, is in unit dosage form
in
an amount of from 25 milligrams to 300 milligrams.
85. The method according to Embodiment 84, wherein valdecoxib, or the
pharmaceutically acceptable salt thereof, is in unit dosage form in an amount
of
from 5 milligrams to 25 milligrams, and the allosteric carboxylic inhibitor of
MMP-l3, or a pharmaceutically acceptable salt thereof, is in unit dosage form
in
an amount of from 25 milligrams to 200 milligrams.
86. The method according to Embodiment 85., wherein valdecoxib, or the
pharmaceutically acceptable salt thereof, is in unit dosage form in an amount
of
from 1 milligram to 5 milligrams, and the allosteric carboxylic inhibitor of
MMP-
l3, or a pharmaceutically acceptable salt thereof, is in unit dosage form in
an
amount of from 25 milligrams to 100 milligrams.
87. A method of treating osteoarthritis in a mammal in need thereof,
comprising administering to the mammal a therapeutically effective amount of a
combination comprising valdecoxib, or a pharmaceutically acceptable salt
thereof,
and an allosteric carboxylic inhibitor of MMP-13, or a pharmaceutically
acceptable salt thereof.
88. The method according to Embodiment 87, wherein the combination is the
combination according to any one of Embodiments 1 to 61.
89. A method of treating osteoarthritis in a mammal in need thereof,
comprising administering to the mammal a therapeutically effective amount of a
pharmaceutical composition, comprising a combination of valdecoxib, or a
pharmaceutically acceptable salt thereof, and an allosteric carboxylic
inhibitor of
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MMP-13, or a pharmaceutically acceptable salt thereof, and a pharmaceutically
acceptable carrier, diluent, or excipient.
90. The method according to Embodiment 89, wherein the combination is the
combination according to any one of Embodiments 1 to 61.
91. The method according to Embodiment 89 or 90, wherein valdecoxib, or
the pharmaceutically acceptable salt thereof, is in unit dosage form in an
amount
of from 1 milligram to 50 milligrams, and the allosteric carboxylic inhibitor
of
MMP-l3, or a pharmaceutically acceptable salt thereof, is in unit dosage form
in
an amount of from 10 milligrams to 600 milligrams.
92. The method according to Embodiment 91, wherein valdecoxib, or the
pharmaceutically acceptable salt thereof, is in unit dosage form in an amount
of
from 5 milligrams to 50 milligrams, and the allosteric carboxylic inhibitor of
MMP-13, or a pharmaceutically acceptable salt thereof, is in unit dosage form
in
an amount of from 10 milligrams to 300 milligrams.
93. The method according to Embodiment 92, wherein valdecoxib, or the
pharmaceutically acceptable salt thereof, is in unit dosage form in an amount
of
from 5 milligrams to 25 milligrams, and the allosteric carboxylic inhibitor of
MMP-13, or a pharmaceutically acceptable salt thereof, is in unit dosage form
in
an amount of from 25 milligrams to 300 milligrams.
94. The method according to Embodiment 93, wherein valdecoxib, or the
pharmaceutically acceptable salt thereof, is in unit dosage form in an amount
of
from 5 milligrams to 25 milligrams, and the allosteric carboxylic inhibitor of
MMP-13, or a pharmaceutically acceptable salt thereof, is in unit dosage form
in
an amount of from 25 milligrams to 200 milligrams.
95. The method according to Embodiment 94, wherein valdecoxib, or the
pharmaceutically acceptable salt thereof, is in unit dosage form in an amount
of
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from 1 milligram to 5 milligrams, and the allosteric carboxylic inhibitor of
MMP-
13, or a pharmaceutically acceptable salt thereof, is in unit dosage form in
an
amount of from 25 milligrams to 100 milligrams.
96. A method of treating rheumatoid arthritis in a mammal in need thereof,
comprising administering to the mammal a therapeutically effective amount of a
combination comprising valdecoxib, or a pharmaceutically acceptable salt
thereof,
and an allosteric carboxylic inhibitor of MMP-13, or a pharmaceutically
acceptable salt thereof.
97. The method according to Embodiment 96, wherein the combination is the
combination according to any one of Embodiments 1 to 61.
98. A method of treating rheumatoid arthritis in a mammal in need thereof,
comprising administering to the mammal a therapeutically effective amount of a
pharmaceutical composition, comprising a combination of valdecoxib, or a
pharmaceutically acceptable salt thereof, and an allosteric carboxylic
inhibitor of
MMP-13, or a pharmaceutically acceptable salt thereof, and a pharmaceutically
acceptable carrier, diluent, or excipient.
99. The method according to Embodiment 98, wherein the combination is the
combination according to any one of Embodiments 1 to 61.
100. The method according to Embodiment 98 or 99, wherein valdecoxib, or
the pharmaceutically acceptable salt thereof, is in unit dosage form in an
amount
of from l milligram to 50 milligrams, and the allosteric carboxylic inhibitor
of
MMP-13, or a pharmaceutically acceptable salt thereof, is in unit dosage form
in
an amount of from 10 milligrams to 600 milligrams.
101. The method according to Embodiment 100, wherein valdecoxib, or the
pharmaceutically acceptable salt thereof, is in unit dosage form in an amount
of
from 5 milligrams to 50 milligrams, and the allosteric carboxylic inhibitor of
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MMP-13, or a pharmaceutically acceptable salt thereof, is in unit dosage form
in
an amount of from 10 milligrams to 300 milligrams.
102. The method according to Embodiment 101, wherein valdecoxib, or the
pharmaceutically acceptable salt thereof, is in unit dosage form in an amount
of
from 5 milligrams to 25 milligrams, and the allosteric carboxylic inhibitor of
MMP-13, or a pharmaceutically acceptable salt thereof, is in unit dosage form
in
an amount of from 25 milligrams to 300 milligrams.
103. The method according to Embodiment 102, wherein valdecoxib, or the
pharmaceutically acceptable salt thereof, is in unit dosage form in an amount
of
from 5 milligrams to 25 milligrams, and the allosteric carboxylic inhibitor of
MMP-13, or a pharmaceutically acceptable salt thereof, is in unit dosage form
in
an amount of from 25 milligrams to 200 milligrams.
104. The method according to Embodiment 103, wherein valdecoxib, or the
pharmaceutically acceptable salt thereof, is in unit dosage form in an amount.
of
from 1 milligram to 5 milligrams, and the allosteric carboxylic inhibitor of
MMP-
13, or a pharmaceutically acceptable salt thereof, is in unit dosage form in
an
amount of from 25 milligrams to 100 milligrams.
105. A method of treating psoriatic arthritis in a mammal in need thereof,
comprising administering to the mammal a therapeutically effective amount of a
combination comprising valdecoxib, or a pharmaceutically acceptable salt
thereof,
and an allosteric carboxylic inhibitor of MMP-13, or a pharmaceutically
acceptable salt thereof.
106. The method according to Embodiment 105, wherein the combination is the
combination according to any one of Embodiments 1 to 61.
107. A method of treating psoriatic arthritis in a mammal in need thereof,
comprising administering to the mammal a therapeutically effective amount of a
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pharmaceutical composition, comprising a combination of valdecoxib, or a
pharmaceutically acceptable salt thereof, and an allosteric carboxylic
inhibitor of
MMP-13, or a pharmaceutically acceptable salt thereof, and a pharmaceutically
acceptable carrier, diluent, or excipient.
108,. The method according to Embodiment 107, wherein the combination is the
combination according to any one of Embodiments 1 to 61.
109. The method according to Embodiment 107 or 108, wherein valdecoxib, or
l0 the pharmaceutically acceptable salt thereof, is in unit dosage form in an
amount
of from 1 milligram to 50 milligrams, and the allosteric carboxylic inhibitor
of
MMP-13, or a pharmaceutically acceptable salt thereof, is in unit dosage form
in
an amount of from 10 milligrams to 600 milligrams.
110. The method according to Embodiment 109, wherein valdecoxib, or the
pharmaceutically acceptable salt thereof, is in unit dosage form in an amount
of
from 5 milligrams to 50 milligrams, and the allosteric carboxylic inhibitor of
MMP-13, or a pharmaceutically acceptable salt thereof, is in unit dosage form
in
an amount of from 10 milligrams to 300 milligrams.
111. The method according to Embodiment 110, wherein valdecoxib, or the
pharmaceutically acceptable salt thereof, is in unit dosage form in an amount
of
from 5 milligrams to 25 milligrams, and the allosteric carboxylic inhibitor of
MMP-13, or a pharmaceutically acceptable salt thereof, is in unit dosage form
in
an amount of from 25 milligrams to 300 milligrams.
112. The method according to Embodiment 111, wherein valdecoxib, or the
pharmaceutically acceptable salt thereof, is in unit dosage form in an amount
of
from 5 milligrams to 25 milligrams, and the allosteric carboxylic inhibitor of
MMP-13, or a pharmaceutically acceptable salt thereof, is in unit dosage form
in
an amount of from 25 milligrams to 200 milligrams.
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113. The method according to Embodiment 112, ~ wherein valdecoxib, or the
pharmaceutically acceptable salt thereof, is in unit dosage form in an amount
of
from 1 milligram to 5 milligrams, and the allosteric carboxylic inhibitor of
MMP-
l3, or a pharmaceutically acceptable salt thereof, is in unit dosage form in
an
amount of from 25 milligrams to 100 milligrams.
114. A method of treating pain in a mammal in need thereof, comprising
administering to the mammal a therapeutically effective amount of a
combination
comprising valdecoxib, or a pharmaceutically acceptable salt thereof, and an
allosteric carboxylic inhibitor of MMP-13, or a pharmaceutically acceptable
salt
thereof.
115. The method according to Embodiment 114, wherein the combination is the
combination according to any one of Embodiments 1 to 61.
116. A method of treating pain in a mammal in need thereof, comprising
administering to the mammal a therapeutically effective amount of a
pharmaceutical composition, comprising a combination of valdecoxib, or a
pharmaceutically acceptable salt thereof, and an allosteric carboxylic
inhibitor of
MMP-13, or a pharmaceutically acceptable salt thereof, and a pharmaceutically
acceptable carrier, diluent, or excipient.
l 17. The method according to Embodiment 116, wherein the combination is the
combination according to any one of Embodiments 1 to 61.
118. The method according to Embodiment 116 or 117, wherein valdecoxib, or
the pharmaceutically acceptable salt thereof, is in unit dosage form in an
amount
of from 1 milligram to SO milligrams, and the allosteric carboxylic inhibitor
of
MMP-13, or a pharmaceutically acceptable salt thereof, is in unit dosage form
in
an amount of from 10 milligrams to 600 milligrams.
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l 19. The method according to Embodiment 118, wherein valdecoxib, or the
pharmaceutically acceptable salt thereof, is in unit dosage form in an amount
of
from 5 milligrams to 50 milligrams, and the allosteric carboxylic inhibitor of
MMP-13, or a pharmaceutically acceptable salt thereof, is in unit dosage form
in
an amount of from 10 milligrams to 300 milligrams.
120. The method according to Embodiment 119, wherein valdecoxib, or the
pharmaceutically acceptable salt thereof, is in unit dosage form in an amount
of
from 5 milligrams to 25 milligrams, and the allosteric carboxylic inhibitor of
MMP-13, or a pharmaceutically acceptable salt thereof, is in unit dosage form
in
an amount of from 25 milligrams to 300 milligrams.
121. The method according to Embodiment 120, wherein valdecoxib, or the
pharmaceutically acceptable salt thereof, is in unit dosage form in an amount
of
from 5 milligrams to 25 milligrams, and the allosteric carboxylic inhibitor of
MMP-13, or a pharmaceutically acceptable salt thereof, is in unit dosage form
in
an amount of from 25 milligrams to 200 milligrams.
122. The method according to Embodiment 121, wherein valdecoxib, or the
pharmaceutically acceptable salt thereof, is in unit dosage form in an amount
of
from 1 milligram to 5 milligrams, and the allosteric carboxylic inhibitor of
MMP-
13, or a pharmaceutically acceptable salt thereof, is in unit dosage form in
an
amount of from 25 milligrams to 100 milligrams.
Another invention embodiment is a combination according to any one of
Embodiments 1 to 61, except where valdecoxib, or the pharmaceutically
acceptable salt thereof, is replaced by celecoxib, or a pharmaceutically
acceptable
salt thereof.
Another invention embodiment is use of any one of the above combination
Embodiments to treat a mammalian disease in a mammal in need of treatment,
wherein the disease is selected from arthritis, rheumatoid arthritis,
osteoarthritis,
osteoporosis, periodontal diseases, inflammatory bowel disease, psoriasis,
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multiple sclerosis, cardiac insufficiency, atherosclerosis, asthma, chronic
obstructive pulmonary disease, age-related macular degeneration, and cancers.
Another invention embodiment is any of the above embodiments of a
combination, comprising an allosteric carboxylic inhibitor of MMP-13, or a
pharmaceutically acceptable salt thereof, wherein the allosteric carboxylic
inhibitor of MMP-13 is any single compound named below in the Examples of
allosteric carboxylic inhibitors of MMP-13, with celecoxib, or a
pharmaceutically
acceptable salt thereof, or valdecoxib, or a pharmaceutically acceptable salt
thereof.
Another invention embodiment is any of the above embodiments of
pharmaceutical compositions, comprising a combination containing an allosteric
carboxylic inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof,
wherein the allosteric carboxylic inhibitor of MMP-13 is any single compound
named below in the Examples of allosteric carboxylic inhibitors of MMP-13,
with
celecoxib, or a pharmaceutically acceptable salt thereof, or valdecoxib, or a
pharmaceutically acceptable salt thereof, together with a pharmaceutically
acceptable carrier, diluent, or excipient.
Another invention embodiment is any of the above embodiments of a
methods of treating a disease in a mammal suffering therefrom, comprising
administering to the mammal a therapeutically effective amount of a
combination,
comprising an allosteric carboxylic inhibitor of MMP-13, or a pharmaceutically
acceptable salt thereof, wherein the allosteric carboxylic inhibitor of MMP-13
is
any single compound named below in the Examples of allosteric carboxylic
inhibitors of MMP-13, with celecoxib, or a pharmaceutically acceptable salt
thereof, or valdecoxib, or a pharmaceutically acceptable salt thereof.
Another invention embodiment is a combination, comprising an allosteric
carboxylic inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof,
wherein the allosteric carboxylic inhibitor of MMP-13 is any single compound
named below in the Examples of allosteric carboxylic inhibitors of MMP-13,
with
celecoxib, or a pharmaceutically acceptable salt thereof, or valdecoxib, or a
pharmaceutically acceptable salt thereof.
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Another invention embodiment is a pharmaceutical composition,
comprising a combination containing an allosteric carboxylic inhibitor of MMP-
13, or a pharmaceutically acceptable salt thereof, wherein the allosteric
carboxylic
inhibitor of MMP-13 is any single compound named below in the Examples of
allosteric carboxylic inhibitors of MMP-13, with celecoxib, or a
pharmaceutically
acceptable salt thereof, or valdecoxib, or a pharmaceutically acceptable salt
thereof, together with a pharmaceutically acceptable carrier, diluent, or
excipient.
Another invention embodiment is a method of treating a disease that is
responsive to inhibition of MMP-13 and to selective inhibition of COX-2 in a
mammal suffering therefrom, comprising administering to the mammal a
therapeutically effective amount of the combination according to any one of
Embodiments 1 to 104.
Another invention embodiment is a method of treating a disease that is
responsive to inhibition of MMP-13 and to selective inhibition of COX-2 in a
mammal suffering therefrom, comprising administering to the mammal a
therapeutically effective amount of a combination, comprising an allosteric
carboxylic inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof,
wherein the allosteric carboxylic inhibitor of MMP-13 is any single compound
named below in the Examples of allosteric carboxylic inhibitors of MMP-13,
with
celecoxib, or a pharmaceutically acceptable salt thereof, or valdecoxib, or a
pharmaceutically acceptable salt thereof.
Another invention embodiment is a method of treating a first disease that
is responsive to inhibition of MMP-13 and a second disease that is responsive
to
selective inhibition of COX-2 in a mammal suffering therefrom, comprising
administering to the mammal a therapeutically effective amount of the
combination according to any one of Embodiments 1 to 104.
Another invention embodiment is a method of treating a first disease that
is responsive to inhibition of MMP-l3 and a second disease that is responsive
to
selective inhibition of COX-2 in a mammal suffering therefrom, comprising
administering to the mammal a therapeutically effective amount of a
combination,
comprising an allosteric carboxylic inhibitor of MMP-13, or a pharmaceutically
acceptable salt thereof, wherein the allosteric carboxylic inhibitor of MMP-13
is
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any single compound named below in the Examples of allosteric carboxylic
inhibitors of MMP-13, with celecoxib, or a pharmaceutically acceptable salt
thereof, or valdecoxib, or a pharmaceutically acceptable salt thereof.
Another invention embodiment is a method of treating an arthritic
condition in a mammal, comprising administering to the mammal an amount of
any one of the above described invention combinations, or any one of the above-
described invention pharmaceutical compositions, sufficient to effectively
treat
the arthritic condition.
Use of a combination comprising valdecoxib, or a pharmaceutically
acceptable salt thereof, and an allosteric carboxylic inhibitor of MMP-13, or
a
pharmaceutically acceptable salt thereof, for the preparation of a medicament
for
treating cartilage damage in a mammal in need thereof.
Use of a combination comprising valdecoxib, or a pharmaceutically
acceptable salt thereof, and an allosteric carboxylic inhibitor of MMP-13, or
a
pharmaceutically acceptable salt thereof, for the preparation of a medicament
for
treating inflammation in a mammal in need thereof.
Use of a combination comprising valdecoxib, or a pharmaceutically
acceptable salt thereof, and an allosteric carboxylic inhibitor of MMP-13, or
a
pharmaceutically acceptable salt thereof, for the preparation of a medicament
for
treating osteoarthritis in a mammal in need thereof.
Use of a combination comprising valdecoxib, or a pharmaceutically
acceptable salt thereof, and an allosteric carboxylic inhibitor of MMP-13, or
a
pharmaceutically acceptable salt thereof, for the preparation of a medicament
for
treating rheumatoid arthritis in a mammal in need thereof.
Use of a combination comprising valdecoxib, or a pharmaceutically
acceptable salt thereof, and an allosteric carboxylic inhibitor of MMP-13, or
a
pharmaceutically acceptable salt thereof, for the preparation of a medicament
for
treating psoriatic arthritis in a mammal in need thereof.
Use of a combination comprising valdecoxib, or a pharmaceutically
acceptable salt thereof, and an allosteric carboxylic inhibitor of MMP-13, or
a
pharmaceutically acceptable salt thereof, for the preparation of a medicament
for
treating pain in a mammal in need thereof.
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DETAILED DESCRIPTION OF THE INVENTION
'
As noted above, the invention provides a combination, comprising an
allosteric carboxylic inhibitor of MMP-13, or a pharmaceutically acceptable
salt
thereof, with celecoxib, or a pharmaceutically acceptable salt thereof, or
valdecoxib, or a pharmaceutically acceptable salt thereof. This invention also
provides a method of treating a disease that is responsive to inhibition of
MMP-13
and cyclooxygenase-2, comprising administering to a patient suffering from
such
a disease the invention combination comprising an allosteric carboxylic
inhibitor
of MMP-13, or a pharmaceutically acceptable salt thereof, with celecoxib, or a
pharmaceutically acceptable salt thereof, or valdecoxib, or a pharmaceutically
acceptable salt thereof. This invention also provides a pharmaceutical
composition, comprising the invention combination comprising an allosteric
carboxylic inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof,
with celecoxib, or a pharmaceutically acceptable salt thereof, or valdecoxib,
or a
pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable
carrier, diluent, or excipient.
The invention combinations may also be further combined with other
pharmaceutical agents depending on the disease being treated.
The terms are as defined below or as they otherwise occur in the
specification.
DEFINITIONS OF TERMS USED TO DEFINE COMPOUNDS OF FORMULA
I:
In Formula I, R1 to R4 include "C1-C6 alkyl" groups. These are straight
and branched carbon chains having from 1 to 6 carbon atoms. Examples of such
alkyl groups include methyl, ethyl, isopropyl, tert-butyl, neopentyl, and n-
hexyl.
The alkyl groups can be substituted if desired, for instance with groups such
as
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hydroxy, amino, alkyl, and dialkylamino, halo, trifluoromethyl, carboxy,
nitro,
and cyano.
Examples of NR4R5 groups include amino, methylamino,
di-isopropylamino, acetyl amino, propionyl amino, 3-aminopropyl amino,
3-ethylaminobutyl amino, 3-di-n-propylamino-propyl amino, 4-diethylaminobutyl
amino, and 3-carboxypropionyl amino. R4 and RS can be taken together with the
nitrogen to which they are attached to form a ring having 3 to 7 carbon atoms
and
l, 2, or 3 heteroatoms selected from the group consisting of nitrogen,
substituted
nitrogen, oxygen, and sulfur. Examples of such cyclic NR4R5 groups include
pyrrolidinyl, piperazinyl, 4-methylpiperazinyl, 4-benzylpiperazinyl,
pyridinyl,
piperidinyl, pyrazinyl, morpholinyl, and the like.
"Halo" includes fluoro, chloro, bromo, and iodo. It should be appreciated
that invention compounds do not include compounds containing an N-halo group.
"Alkenyl" means straight and branched hydrocarbon radicals having from
2 to 6 carbon atoms and one double bond and includes ethenyl, 3-buten-1-yl,
2-ethenylbutyl, 3-hexen-1-yl, and the like.
"Alkynyl" means straight and branched hydrocarbon radicals having from
2 to 10 carbon atoms and one triple bond and includes ethynyl, 3-butyn-1-yl,
propynyl, 2-butyn-1-yl, 3-pentyn-1-yl, 1-hexyn-1-yl, 7,7-dimethyl-1-octyn-1-
yl,
and the like.
"Cycloalkyl" means a monocyclic or polycyclic hydrocarbyl group such as
cyclopropyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclobutyl, adamantyl,
norpinanyl, decalinyl, norbornyl, cyclohexyl, and cyclopentyl. Such groups can
be
substituted with groups such as hydroxy, keto, and the like. Examples of
substituted cycloalkyl include 4-carboxycyclohexyl, 4-oxo-cyclohexyl,
4-(carboxymethyl)-cyclobutyl, 3-methyl-cyclopentyl, and
3-(carboxymethyl)cyclopentyl. Also included are rings in which 1 to
3 heteroatoms replace carbons. Such groups are termed "heterocycle" or
"heterocyclyl", which mean a cycloalkyl group also bearing at least one
heteroatom selected from O, S, or NR2, examples being oxiranyl, pyrrolidinyl,
4-methylpiperazinyl, piperidyl, tetrahydropyranyl, and morpholinyl. The group
R2
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here is as defined above for Formula I, except where R2 contains the
functional
group "NRSR6", the groups RS and R6 are not taken together with the nitrogen
atom to which they are attached to complete a 3- to 7-membered ring.
"Alkoxy" refers to the alkyl groups mentioned above bound through
oxygen, examples of which include methoxy, ethoxy, isopropoxy, tert-butoxy,
and
the like. In addition, alkoxy refers to polyethers such as -O-(CH2)2-O-CH3,
and
the like.
"Alkanoyl" groups are alkyl linked through a carbonyl, i.e., C1-CS-C(O)-.
Such groups include formyl, acetyl, propionyl, butyryl, and isobutyryl.
"Acyl" means an alkyl or aryl (Ar) group bonded through a carbonyl
group, i.e., R-C(O)-. For example, acyl includes a Cl-C6 alkanoyl, including
substituted alkanoyl, wherein the alkyl portion can be substituted by NR4R5 or
a
carboxylic or heterocyclic group. Typical acyl groups include acetyl, benzoyl,
and
the like.
The alkyl, alkenyl, alkoxy, and alkynyl groups described above are
optionally substituted, preferably by 1 to 3 groups selected from NR4R5,
phenyl,
substituted phenyl, heteroaryl, substituted heteroaryl, heterocycle, thio
Cl-C6 alkyl, Cl-C6 alkoxy, hydroxy, carboxy, C1-C6 alkoxycarbonyl, halo,
nitrite, cycloalkyl, and a 5- or 6-membered carbocyclic ring or heterocyclic
ring
having 1 or 2 heteroatoms selected from nitrogen, substituted nitrogen,
oxygen,
and sulfur. "Substituted nitrogen" means nitrogen bearing C1-C6 alkyl or
(CH2)nPh where n is l, 2, or 3. Perhalo and polyhalo substitution is also
embraced.
Examples of substituted alkyl groups include 2-aminoethyl,
pentachloroethyl, trifluoromethyl, 2-diethylaminoethyl, 2-dimethylaminopropyl,
ethoxycarbonylmethyl, 3-phenylbutyl, methanylsulfanylmethyl, methoxymethyl,
'3-hydroxypentyl, 2-carboxybutyl, 4-chlorobutyl, 3-cyclopropylpropyl,
pentafluoroethyl, benzyl(Bn), 3-morpholinopropyl, piperazinylmethyl, pyridyl-
4-methyl(Py-4-me), 3-(pyridyl-4-thio)propyl, and 2-(4-methylpiperazinyl)ethyl.
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Examples of substituted alkynyl groups include 2-methoxyethynyl,
2-ethylsulfanyethynyl, 4-(1-piperazinyl)-3-(butynyl), 3-phenyl-5-hexynyl,
3-diethylamino-3-butynyl, 4-chloro-3-butynyl, 4-cyclobutyl-4-hexenyl, and the
like.
Typical substituted alkoxy groups include aminomethoxy,
trifluoromethoxy, 2-diethylaminoethoxy, 2-ethoxycarbonylethoxy,
3-hydroxypropoxy, 6-carboxhexyloxy, and the like.
Further, examples of substituted alkyl, alkenyl, and alkynyl groups include
dimethylaminomethyl, carboxymethyl, 4-dimethylamino-3-buten-1-yl,
5-ethylmethylamino-3-pentyn-1-yl, 3-(3-methoxyphenyl)-propyn-1-yl, 3-(3,4-
difluorophenyl)-propyn-1-yl, 4-morpholinobutyl, 4-tetrahydropyrinidylbutyl,
3-imidazolidin-1-ylpropyl, 4-tetrahydrothiazol-3-yl-butyl, phenylmethyl,
3-chlorophenylmethyl, and the like.
The terms "Ar" and "aryl" refer to unsubstituted and substituted aromatic
groups. Heteroaryl groups have from 4 to 10 ring atoms, from 1 to 4 of which
are
independently selected from the group consisting of O, S, and N. Preferred
heteroaryl groups have 1 or 2 heteroatoms in a 5- or 6-membered aromatic ring.
Mono- and bicyclic aromatic ring systems are included in the definition of
aryl
and heteroaryl. Typical aryl groups include phenyl and naphthyl. Typical
substituted aryl groups include 3,4-difluorophenyl, 4-carboxyphenyl, 3,4-
methylenedioxyphenyl, 4-carboxymethylphenyl, 3-methoxyphenyl, and 7-fluoro-
1-naphthyl. Typical heteroaryl groups include pyridyl, thienyl, benzothienyl,
indolyl, furanyl, thiazolyl, isothiazolyl, indazolyl, 2-oxo-2H-l-benzopyranyl,
and
imidazolyl. Typical substituted heteroaryl groups include 3-methoxy-
isothiazolyl,
3-methoxypyridin-4-yl, 4-ethylbenzothienyl, 4-thiopyridyl, 2-methoxy-pyridin-
4-yl, l-methylpyrazol-4-yl, and 2-methyl-pyridin-3-yl.
Preferred Ar groups are phenyl and phenyl substituted by l, 2, or 3 groups
independently selected from alkyl, alkoxy, alkoxycarbonyl, thio, thioalkyl,
(C1-C6 alkyl)sulfanyl, (C1-C6 alkyl)sulfonyl, halo, hydroxy, (CH2)0-6C02R~,
trifluoromethyl, trifluoromethoxy, nitro, amino of the formula -NR4R5,
C(=O)NRSR6, N(R4)C(=O)ORS, and T(CH2)mQR4 or T(CH2)mC02R4,
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wherein m is 1 to 6, T is O, S, NR4, N(O)R4, NR4R6Y, or CR4R5, Q is O, S,
NRS, N(O)R5, or NRSR6Y, wherein R4-R6 are as described above, and R~ is
hydrogen, alkyl, or substituted alkyl, for example, methyl, trichloroethyl,
diphenylmethyl, and the like. The alkyl and alkoxy groups can be substituted
as
defined above. For example, typical groups are carboxyalkyl,
alkoxycarbonylalkyl, hydroxyalkyl, hydroxyalkoxy, and alkoxyalkyl. Examples of
substituted phenyl are 3-methoxyphenyl, 2,6-dichlorophenyl, 3-nitrophenyl,
4-dimethylaminophenyl, and biphenyl.
Preferred heteroaryl groups include thienyl, furanyl, pyrrolyl, isoxazolyl,
isothiazolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, 1,2,4-oxadiazolyl,
1,2,4,-thiadiazolyl, 1,2,4-triazolyl, tetrazolyl, benzofuranyl, benzothienyl,
indolyl,
benzimidazolyl, benzotriazolyl, benzoxazolyl, benzthiazolyl, pyridinyl,
pyrimidinyl, quinolinyl, isoquinolinyl, and 2-oxo-2H-1-benzopyranyl.
Preferred heteroaryl groups may be substituted on a carbon atom as
described above for substituted phenyl, and may further be substituted on a
ring
nitrogen atom (i.e., by replacing a hydrogen from a ring nitrogen atom, which
is
an NH group) with (C1-C6 alkyl) C(=O), C1-C6 alkyl, C2-C6 alkenyl, C2-Clp
alkynyl, or benzyl.
DEFINITIONS OF TERMS USED TO DEFINE COMPOUNDS OF FORMULA
IA:
In Formula IA, Rl to R9 include "C1-C6 alkyl" groups. Alkyl groups are
straight and branched carbon chains having from 1 to 6 carbon atoms. Examples
of such alkyl groups include methyl, ethyl, isopropyl, tert-butyl, neopentyl,
and
n-hexyl. The alkyl groups can be substituted if desired, for instance with
groups
such as hydroxy, amino, alkyl, and dialkylamino, halo, trifluoromethyl,
carboxy,
nitro, and cyano.
Examples of NR4R5 groups include amino, methylamino,
di-isopropylamino, acetyl amino, propionyl amino, 3-aminopropyl amino,
3-ethylaminobutyl amino, 3-di-n-propylamino-propyl amino, 4-diethylaminobutyl
amino, and 3-carboxypropionyl amino. R4 and RS can be taken together with the
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nitrogen to which they are attached to form a ring containing from 3 to 7
carbon
atoms and l, 2, or 3 heteroatoms selected from the group consisting of
nitrogen,
substituted nitrogen, oxygen, and sulfur. Examples of such cyclic NR4R5 groups
include pyrrolidinyl, piperazinyl, 4-methylpiperazinyl, 4-benzylpiperazinyl,
pyridinyl, piperidinyl, pyrazinyl, morpholinyl, and the like.
"Halo" includes fluoro, chloro, bromo, and iodo.
"Alkenyl" means straight and branched hydrocarbon radicals having from
2 to 6 carbon atoms and one double bond and includes ethenyl, 3-buten-1-yl,
2-ethenylbutyl, 3-hexen-1-yl, and the like.
"Alkynyl" means straight and branched hydrocarbon radicals having from
2 to 6 carbon atoms and one triple bond and includes ethynyl, 3-butyn-1-yl,
propynyl, 2-butyn-1-yl, 3-pentyn-1-yl, and the like.
"Cycloalkyl" means a monocyclic or polycyclic hydrocarbyl group such as
cyclopropyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclobutyl, adamantyl,
norpinanyl, decalinyl, norbornyl, cyclohexyl, and cyclopentyl. Such groups can
be
substituted with groups such as hydroxy, keto, and the like. Also included are
rings in which 1 to 3 heteroatoms replace carbons. Such groups are termed
"heterocyclyl," which means a cycloalkyl group also bearing at least one
heteroatom selected from O, S, or NR2, examples being oxiranyl, pyrrolidinyl,
piperidyl, tetrahydropyran, and morpholine.
"Alkoxy" refers to the alkyl groups mentioned above bound through
oxygen, examples of which include methoxy, ethoxy, isopropoxy, tert-butoxy,
and
the like. In addition, alkoxy refers to polyethers such as -O-(CH2)2-O-OH3,
and
the like.
"Acyl" means an R group that is a CI-C6 alkyl or aryl (Ar) group bonded
through a carbonyl group, i.e., R-C(O)-, where R is alkyl or aryl. For
example,
acyl includes a Cl-C6 alkanoyl, including substituted alkanoyl, wherein the
alkyl
portion can be substituted by NR4R5 or a carboxylic or heterocyclic group.
Typical acyl groups include acetyl, benzoyl, isonicotinoyl, and the like.
The alkyl, alkenyl, alkoxy, and alkynyl groups described above are
optionally substituted, preferably by 1 to 3 groups selected from NR4R5,
phenyl,
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substituted phenyl, thio C1-C6 alkyl, C1-C6 alkoxy, hydroxy, carboxy, C1-C6
alkoxycarbonyl, acyl, halo, nitrile, cycloalkyl, and a 5- or 6-membered
carbocyclic ring or heterocyclic ring having 1 or 2 heteroatoms selected from
nitrogen, substituted nitrogen, oxygen, and sulfur. "Substituted nitrogen"
means
nitrogen bearing C1-C6 alkyl or (CH2)nPh where n is l, 2, or 3. Perhalo and
polyhalo substitution is also embraced.
Examples of substituted alkyl groups include 2-aminoethyl, acetylmethyl,
pentachloroethyl, trifluoromethyl, 2-diethylaminoethyl, 2-dimethylaminopropyl,
ethoxycarbonylmethyl, 3-phenylbutyl, methanylsulfanylmethyl, methoxymethyl,
l0 3-hydroxypentyl, 2-carboxybutyl, 4-chlorobutyl, 3-cyclopropylpropyl,
pentafluoroethyl, 3-morpholinopropyl, piperazinylmethyl, 4-benzoylbutyl, and
2-(4-methylpiperazinyl)ethyl.
Examples of substituted alkynyl groups include 2-methoxyethynyl,
2-benzoylethylyl, 2-ethylsulfanyethynyl, 4-(1-piperazinyl)-3-(butynyl), 3-
phenyl
5-hexynyl, 3-diethylamino-3-butynyl, 4-chloro-3-butynyl, 4-cyclobutyl
4-hexenyl, and the like.
Typical substituted alkoxy groups include aminomethoxy,
acetoxymethoxy, trifluoromethoxy, 2-diethylaminoethoxy,
2-ethoxycarbonylethoxy, 3-hydroxypropoxy, 6-carboxhexyloxy, and the like.
Further, examples of substituted alkyl, alkenyl, and alkynyl groups include
dimethylaminomethyl, carboxymethyl, 4-dimethylamino-3-buten-1-yl,
5-ethylmethylamino-3-pentyn-1-yl, 4-morpholinobutyl,
4-tetrahydropyrinidylbutyl, 3-imidazolidin-1-ylpropyl, 4-tetrahydrothiazol-
3-yl-butyl, phenyl methyl, 3-chlorophenylmethyl, and the like.
The terms "Ar" and "aryl" refer to unsubstituted and substituted aromatic
groups. Heteroaryl groups have from 4 to 10 ring atoms, from 1 to 4 of which
are
independently selected from the group consisting of O, S, and N. Preferred
heteroaryl groups have 1 or 2 heteroatoms in a 5- or 6-membered aromatic ring.
Mono- and bicyclic aromatic ring systems are included in the definition of
aryl
and heteroaryl. A bicyclic aryl group is naphthyl for example. Bicyclic
heteroaryl
groups include indolyl and benzothienyl, to name a few. Preferred substituent
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groups include alkyl, alkoxy, halo, amino, alkylamino, dialkylamino, CN, CF3,
thioalkyl, acyl and hydroxy. Typical aryl and heteroaryl groups include
phenyl,
3-chlorophenyl, 2,6-dibromophenyl, pyridyl, 3-methylpyridyl, benzothienyl,
2,4,6-tribromophenyl, 4-ethylbenzothienyl, furanyl, 3,4-diethylfuranyl,
naphthyl,
4,7-dichloronaphthyl, morpholinyl, indolyl, benzotriazolyl, indazolyl,
pyrrole,
pyrazole, imidazole, thiazole, methylenedioxyphenyl, benzo-2,1,3-thiadiazole,
benzo-2,1,3-oxadiazole, and the like.
Preferred Ar groups are phenyl and phenyl substituted by 1, 2, or 3 groups
independently selected from the group consisting of alkyl, alkoxy, thio,
thioalkyl,
halo, hydroxy, -COOR7, trifluoromethyl, vitro, amino of the formula -NR4R5,
and T(CH2)mQR4 or T(CH2)mC02R4 wherein m is 1 to 6, T is O, S, NR4,
N(O)R4, NR4R6Y, or CR4R5, Q is O, S, NRS, N(O)R5, or NRSR6Y wherein
R4 and RS are as described above, and R7 is H, alkyl or substituted alkyl, for
example, methyl, trichloroethyl, diphenylmethyl, and the like. The alkyl and
alkoxy groups can be substituted as defined above. For example, typical groups
are carboxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, hydroxyalkoxy, and
alkoxyalkyl. Typical substituted aryl groups include 2,6-dichlorophenyl,
3-hydroxyphenyl, 1,3-benzodioxolyl, 4-dimethylaminophenyl,
2,4,6-triethoxyphenyl, 3-cyanophenyl, 4-methylthiophenyl, and 3,5-
dinitrophenyl.
The term "substituted", unless otherwise defined, includes from 1 to
3 substituents selected from:
C1-C6 alkyl; C2-C6 alkenyl; C2-C6 alkynyl; C1-C6 alkoxy; phenyl;
(C1-C6 alkoxy)carbonyl; (C1-C6 alkyl)sulfanyl; (C1-C6 alkyl)carbonyl;
OH; NH2; N(H)R4, wherein R4 is as defined above for Formula IA;
NR4R5, wherein R4 and RS are as defined above for Formula IA, or R4
and RS are taken together with the nitrogen atom to which they are
attached to form a 3- to 7-membered saturated ring containing carbon
atoms and optionally from 1 or 2 heteroatoms selected from O, S, S(O),
S(O)2, N(H), and N(C1-C6 alkyl), wherein the ring may be optionally
substituted on a carbon atom with 1 oxo (i.e., =O) group;
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C(=O)NR4R5, wherein R4 and RS are as defined immediately above, or
R4 and RS are taken together with the nitrogen atom to which they are
attached to form a 3- to 7-membered saturated ring containing carbon
atoms and optionally 1 or 2 heteroatoms selected from O, S, S(O), S(O)2,
f N(H), and N(C1-C6 alkyl), wherein the ring may be optionally substituted
on a carbon atom with 1 oxo (i.e., =O) group;
CN; N02; CF3; C02H; CHO; SH; (C1-C6alkyl) S(O);
(Cl-C6 alkyl)sulfonyl; halo; S(O)2NR4R5, wherein R4 and RS are as
defined above for Formula IA, or R4 and RS are taken together with the
nitrogen atom to which they are attached to form a 3- to 7-membered
saturated ring containing carbon atoms and optionally 1 or 2 heteroatoms
selected from O, S, S(O), S(O)2, N(H), and N(Cl-C6 alkyl), wherein the
ring may be optionally substituted on a carbon atom with 1 oxo (i.e., =O)
group;
OCF3; and (CH2)mC02H, wherein m is as defined above for Formula IA.
DEFINITIONS OF TERMS USED TO DEFINE COMPOUNDS OF FORMULA
IB:
In Formula IB, Rl-R4 include "Cl-C6 alkyl" groups. These are straight
and branched carbon chains having from 1 to 6 carbon atoms. Examples of such
alkyl groups include methyl, ethyl, isopropyl, tert-butyl, neopentyl, and n-
hexyl.
The alkyl groups can be substituted if desired, for instance, with groups such
as
aryl-O-, wherein aryl is as defined below, heteroaryl-O-, wherein heteroaryl
is as
defined below, hydroxy, amino, alkyl, and dialkylamino, halo, trifluoromethyl,
carboxy, vitro, and cyano. Typical substituted alkyl groups thus are
aminomethyl,
2-nitroethyl, 4-cyanobutyl, 2,3-dichloropentyl, and 3-hydroxy-5-carboxyhexyl.
Examples of NR4R5 groups include amino, methylamino,
di-isopropylamino, acetyl amino, propionyl amino, 3-aminopropyl amino,
3-ethylaminobutyl amino, 3-di-n-propylamino-propyl amino, 4-diethylaminobutyl
amino, and 3-carboxypropionyl amino. R4 and RS can be taken together with the
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nitrogen to which they are attached to form a ring having 3 to 7 carbon atoms
and
l, 2, or 3 heteroatoms selected from the group consisting of nitrogen,
substituted
nitrogen, oxygen, and sulfur. Examples of such cyclic NR4R5 groups include
pyrrolidinyl, piperazinyl, 4-methylpiperazinyl, 4-benzylpiperazinyl,
pyridinyl,
piperidinyl, pyrazinyl, morpholinyl, and the like.
"Halo" includes fluoro, chloro, bromo, and iodo.
"Alkenyl" means straight and branched hydrocarbon radicals having from
2 to 6 carbon atoms and one double bond 'and includes ethenyl, 3-buten-1-yl,
2-ethenylbutyl, 3-hexen-1-yl, and the like.
"Alkynyl" means straight and branched hydrocarbon radicals having from
2 to 6 carbon atoms and one triple bond and includes ethynyl, 3-butyn-1-yl,
propynyl, 2-butyn-1-yl, 3-pentyn-1-yl, and the like.
"Carbocycle" or "Cycloalkyl" mean a monocyclic or polycyclic
hydrocarbyl group such as cyclopropyl, cycloheptyl, cyclooctyl, cyclodecyl,
cyclobutyl, adamantyl, norpinanyl, decalinyl, norbornyl, cyclohexyl, and
cyclopentyl. Such groups can be substituted with groups such as hydroxy, keto,
and the like. Also included are rings in which 1 to 3 heteroatoms replace
carbons.
Such groups are termed "heterocycle" or "heterocyclic" or "heterocyclyl,"
which
mean a cycloalkyl group also bearing at least one heteroatom selected from O,
S,
or NR2, examples being oxiranyl, pyrrolidinyl, piperidyl, tetrahydropyran, and
morpholine.
"Alkoxy" refers to the alkyl groups mentioned above bound through
oxygen, examples of which include methoxy, ethoxy, isopropoxy, tert-butoxy,
and
the like. In addition, alkoxy refers to polyethers such as -O-(CH2)2-O-OH3,
and
the like.
"Alkanoyl" groups are alkyl linked through a carbonyl, ie, C1-CS-C(O)-.
Such groups include formyl, acetyl, propionyl, butyryl, and isobutyryl.
"Acyl" means an alkyl or aryl (Ar) group bonded through a carbonyl
group, i.e., R-C(O)-. For example, acyl includes a C1-C6 alkanoyl, including
substituted alkanoyl, wherein the alkyl portion can be substituted by NR4R5 or
a
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carboxylic or heterocyclic group. Typical acyl groups include acetyl, benzoyl,
and
the like.
The alkyl, alkenyl, alkoxy, and alkynyl groups described above are
optionally substituted, preferably by 1 to 3 groups selected from NR4R5,
phenyl,
substituted phenyl, thio Cl-C6 alkyl, Cl-C6 alkoxy, hydroxy, carboxy, aryl-O-,
wherein aryl is as defined below, heteroaryl-O-, wherein heteroaryl is as
defined
below, Cl-C6 alkoxycarbonyl, halo, nitrile, cycloalkyl, and a 5- or 6-membered
carbocyclic ring or heterocyclic ring having 1 or 2 heteroatoms selected from
nitrogen, substituted nitrogen, oxygen, and sulfur. "Substituted nitrogen"
means
l0 nitrogen bearing Cl-C6 alkyl or (CH2)nPh where n is l, 2, or 3. Perhalo and
polyhalo substitution is also embraced. Oxo (=O) substitution of a CH2 carbon
group to provide a carbonyl (C=O) is also embraced.
Examples of substituted alkyl groups include 2-aminoethyl,
pentachloroethyl, trifluoromethyl, 2-diethylaminoethyl, 2-dimethylaminopropyl,
' 15 ethoxycarbonylmethyl, 3-phenylbutyl, methanylsulfanylmethyl,
methoxymethyl,
3-hydroxypentyl, 2-carboxybutyl, 4-chlorobutyl, 3-cyclopropylpropyl,
pentafluoroethyl, 3-morpholinopropyl, piperazinylmethyl, and
2-(4-methylpiperazinyl)ethyl.
Examples of substituted alkynyl groups include 2-methoxyethynyl,
20 2-ethylsulfanyethynyl, 4-(1-piperazinyl)-3-(butynyl), 3-phenyl-5-hexynyl,
3-diethylamino-3-butynyl, 4-chloro-3-butynyl, 4-cyclobutyl-4-hexenyl, and the
like.
Typical substituted alkoxy groups include aminomethoxy,
trifluoromethoxy, 2-diethylaminoethoxy, 2-ethoxycarbonylethoxy,
25 3-hydroxypropoxy, 6-carboxhexyloxy, and the like.
Further, examples of substituted alkyl, alkenyl, and alkynyl groups include
dimethylaminomethyl, carboxymethyl, 4-dimethylamino-3-buten-1-yl,
5-ethylmethylamino-3-pentyn-I -yl, 4-morpholinobutyl,
4-tetrahydropyrinidylbutyl, 3-imidazolidin-1-ylpropyl, 4-tetrahydrothiazol-
30 3-yl-butyl, phenylmethyl, 3-chlorophenylmethyl, and the like.
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The terms "Ar" and "aryl" refer to unsubstituted and substituted aromatic
groups. Heteroaryl groups have from 4 to 10 ring atoms which are carbon atoms,
and from 1 to 4 of which are independently selected from the group consisting
of O, S, and N. Preferred heteroaryl groups have 1 or 2 heteroatoms in a 5- or
6-membered aromatic ring. Mono and bicyclic aromatic ring systems are included
in the definition of aryl and heteroaryl. Typical aryl and heteroaryl groups
include
phenyl, 3-chlorophenyl, 2,6-dibromophenyl, pyridyl, 3-methylpyridyl,
benzothienyl, 2,4,6-tribromophenyl, 4-ethylbenzothienyl, furanyl,
3,4-diethylfuranyl, naphthyl, 4,7-dichloronaphthyl, morpholinyl, indolyl,
benzotriazolyl, indazolyl, pyrrole, pyrazole, imidazole, thiazole, and the
like.
Preferred Ar groups are phenyl and phenyl substituted by 1, 2, or 3 groups
independently selected from the group consisting of alkyl, alkoxy, thio,
thioalkyl,
1H-tetrazol-5-yl, halo, hydroxy, -COOR6, trifluoromethyl, nitro, amino of the
formula -NR4R5, and T(CH2)mQR4 or T(CH2)mC02R4 wherein m is 1 to 6, T
is O, S, NR4, N(O)R4, NR4RSY, or CR4R5, Q is O, S, NRS, N(O)R5, or
NR4RSY wherein R4 and RS are as described above, and R6 is hydrogen, alkyl,
or substituted alkyl, for example, methyl, trichloroethyl, diphenylmethyl, and
the
like. The alkyl and alkoxy groups can be substituted as defined above. For
example, typical groups are carboxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl,
hydroxyalkoxy, and alkoxyalkyl. Typical substituted aryl groups include
2,6-dichlorophenyl, 3-methoxyphenyl, 4-trifluoromethylphenyl, 4-styrylphenyl,
3-amino-4-nitrophenyl, 3,5-dihydroxyphenyl, and the like.
Most preferred aryl is phenyl, 4- or 3-methoxy-phenyl, 4-fluorophenyl,
and 3-fluorophenyl, and each of 3,4-disubstituted phenyls wherein the
substituents
are methoxy and fluoro. '
Most preferred heteroaryl is pyridin-4-yl or 2-methoxypyridin-4-yl.
DEFINITIONS OF TERMS USED TO DEFINE COMPOUNDS OF FORMULA
IC:
In Formula IC,:
The term "halogen" means F, Cl, Br, or I; preferably F, Br and Cl.
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The term "(C~-C6)alkyl" means linear or branched alkyl containing from 1
to 6, and preferably from 1 to 3 carbon atoms.
The term "(C~-C6)alkoxy" means linear or branched alkyl containing from
1 to 6, and preferably from 1 to 3, carbon atoms bonded through an oxygen
atom.
' The term "(C3-C6)alkenyl" means an alkenyl containing from 3 to 6, and
preferably 3 or 4 carbon atoms, more particularly allyl.
The teen "(C3-C6)alkynyl" means alkynyl containing from 3 to 6, and
preferably 3 or 4, carbon atoms, more particularly propargyl.
The term "aryl" means an aromatic ring containing from 5 to 10, and
l0 preferably 5 or 6, carbon atoms.
The teen "heteroaryl" means a heteroaromatic aryl group interrupted with
one or several hetero atom selected from nitrogen, oxygen and sulphur. The
term
"interrupted" means that the hetero atom can replace a carbon atom of the
ring.
Examples of such groups containing a heteroatom are, inter alia, thienyl,
pyridyl,
benzofurazanyl.
The term "heterocycle" means an aromatic or non-aromatic, 5-or 6-
membered monocycle comprising carbon atoms and from 1 to 4 heteroatoms
selected from nitrogen, oxygen and sulphur.
The term "aryl(C~-C6)alkyl" means an aryl, as defined above, bonded
through an alkyl, wherein the alkyl contains from 1 to 6, and preferably from
1 to
4, carbon atoms.
The term "cycloalkyl" means a cycloalkyl containing from 3 to 8, and
preferably from 3 to 6, carbon atoms.
The term "cycloalkyl(C~-C6)alkyl" means a cycloalkyl group bonded
through an alkyl group, wherein the alkyl contains from 1 to 6, and preferably
from 1 to 3, carbon atoms and the cycloalkyl contains from 3 to 6 carbon
atoms.
The phrase "multiple bond" represents a double bond or a triple bond.
DEFINITIONS OF TERMS USED TO DEFINE COMPOUNDS OF FORMULA
ID:
The term "halogen" means F, C1, Br, or I; preferably F, Br and C1.
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The term "(C,-C6)alkyl" means linear or branched alkyl containing from 1
to 6, and preferably from 1 to 3 carbon atoms.
The term "halo(C~-C6)alkyl" means (C~-C6)alkyl as defined above
substituted with one or more halogen atoms, and preferably trihalogenomethyl.
The term "(C,-C6)alkoxy" means linear or branched alkyl containing from
1 to 6, and preferably from 1 to 3, carbon atoms bonded through an oxygen
atom.
The term "(C3-C6)alkenyl" means an alkenyl containing from 3 to 6, and
preferably 3 or 4 carbon atoms, more particularly allyl.
The term "(C3-C6)alkynyl" means alkynyl containing from 3 to 6, and
preferably 3 or 4, carbon atoms, more particularly propargyl.
The term "aryl" means an aromatic ring containing from 5 to 10, and
preferably 5 or 6, carbon atoms.
The term "heteroaryl" means a heteroaromatic aryl group interrupted with
one or several hetero atom selected from nitrogen, oxygen and sulphur. The
term
"interrupted" means that the hetero atom can replace a carbon atom of the
ring.
Examples of such groups containing a heteroatom are, inter alia, thienyl,
pyridyl,
benzofurazanyl.
The term "heterocycle" means an aromatic or non-aromatic, 5-or 6-
membered monocycle comprising carbon atoms and from 1 to 4 heteroatoms
selected from nitrogen, oxygen and sulphur.
The term "aryl(C~-C6)alkyl" means an aryl, as defined above, bonded
through an alkyl, wherein the alkyl contains from 1 to 6, and preferably from
1 to
4, carbon atoms.
The term "cycloalkyl" means a cycloalkyl containing from 3 to 8, and
preferably from 3 to 6, carbon atoms.
The term "cycloalkyl(C~-C6)alkyl" means a cycloalkyl group bonded
through an alkyl group, wherein the alkyl contains from 1 to 6, and preferably
from 1 to 3, carbon atoms and the cycloalkyl contains from 3 to 6 carbon
atoms.
The phrase "multiple bond" represents a double bond or a triple bond.
DEFINITIONS OF TERMS USED TO DEFINE COMPOUNDS OF FORMULA
IE:
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In Formula IE, Rl to R3 include "CI-C6 alkyl" groups. These are straight
and branched carbon chains having from 1 to 6 carbon atoms. Examples of such
alkyl groups include methyl, ethyl, isopropyl, tert-butyl, neopentyl, and n-
hexyl.
The alkyl groups can be substituted if desired, for instance with groups such
as
hydroxy, alkoxy, amino, alkyl and dialkylamino, alkanoyl, acyl, halo,
trifluoromethyl, carboxy, nitro, and cyano.
"Alkenyl" means straight and branched hydrocarbon radicals having from
2 to 6 carbon atoms and one double bond and includes ethenyl, 3-buten-1-yl,
2-ethenylbutyl, 3-hexen-1-yl, and the like.
"Alkynyl" means straight and branched hydrocarbon radicals having from
2 to 6 carbon atoms and one triple bond and includes ethynyl, 3-butyn-1-yl,
propynyl, 2-butyn-I-yl, 3-pentyn-1-yl, and the like.
"Cycloalkyl" means a monocyclic or polycyclic hydrocarbyl group such as
cyclopropyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclobutyl, adamantyl,
norpinanyl, decalinyl, norbornyl, cyclohexyl, and cyclopentyl. Such groups can
be
substituted with groups such as hydroxy, keto, and the like. Also included are
rings in which 1 to 3 heteroatoms replace carbons. Such groups are termed
"heterocycle" or "heterocyclyl", which means a cycloalkyl group also bearing
at
least one heteroatom selected from O, S, or NR2, examples being oxiranyl,
pyrrolidinyl, piperidyl, tetrahydropyran, and morpholine.
"Alkoxy" refers to the alkyl groups mentioned above bound through
oxygen, examples of which include methoxy, ethoxy, isopropoxy, tert-butoxy,
and
the like. In addition, alkoxy refers to polyethers such as -O-(CH2)2-O-CH3,
and
the like. "Thioalkoxy" is an alkoxy group wherein the O is replaced by an S.
"Alkanoyl" groups are alkyl linked through a carbonyl, ie, CI-CS-C(O)-.
Such groups include formyl, acetyl, propionyl, butyryl, and isobutyryl.
"Acyl" means an R group that is a CI-C6 alkyl or aryl ~(Ar) group bonded
through a carbonyl group, i.e., R-C(O)-, wherein CI-C6 alkyl and aryl are as
defined above and below, respectively. The phrase "substituted acyl" means an
R
group that is a substituted CI-C6 alkyl or a substituted aryl (substituted Ar)
group
bonded through a carbonyl group. For example, substituted acyl includes
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substituted alkanoyl, wherein the alkyl portion can be substituted by NR4R5 or
a
carboxylic or heterocyclic group. Typical acyl groups include acetyl, benzoyl,
and
the like. Typical substituted acyl groups include trifluoroacetyl,
4-carboxybenzoyl, and the like.
The alkyl, alkenyl, alkoxy, and alkynyl groups described above are
optionally substituted, preferably by 1 to 3 groups selected from NR4R5,
phenyl,
substituted phenyl, (CH2)m-C(O) phenyl, (CH2)m C(O) substituted phenyl,
(CH2)m-S(O)p_2 phenyl, (CH2)m S(O)p-2 substituted phenyl,
(CH2)m-C(O) heteroaryl, (CH2)m C(O) substituted heteroaryl,
(CH2)m-S(O)p_2 heteroaryl, (CH2)m-S(O)p_2 substituted heteroaryl,
(CH2)m cycloalkyl, heterocycle, thio C1-C6 alkyl, C1-C6 alkoxy, hydroxy, acyl,
carboxy, alkanoyl, Cl-Cg alkoxycarbonyl, halo, nitro, nitrile, cycloalkyl, and
a 5-
or 6-membered carbocyclic ring or heterocyclic ring having 1 or 2 heteroatoms
selected from nitrogen, substituted nitrogen, oxygen, and sulfur. "Substituted
l5 nitrogen" means nitrogen bearing C1-C6 alkyl or (CH2)yPh where y is 1, 2,
or 3.
Perhalo and polyhalo substitution is also embraced.
R4 and RS independently are hydrogen, C1-C6 alkyl, C2-C6 alkenyl,
C2-C6 alkynyl, acyl, (CH2)m aryl, (CH2)m heteroaryl, (CH2)m cycloalkyl,
wherein these groups may be unsubstituted or substituted as described herein,
or
R4 and RS are taken together with the nitrogen atom to which they are attached
to
form a 3- to 7-membered ring containing carbon atoms, the nitrogen atom
bearing
R4 and R5, and optionally 1 or 2 heteroatoms selected from O, S, NH, and NR2,
wherein R2 is as defined above, the ring optionally may be substituted with
oxo
("=O") on a carbon atom.
Examples of NR4R5 groups include amino, methylamino,
di-isopropylamino, acetyl amino, propionyl amino, 3-aminopropyl amino,
3-ethylaminobutyl amino, 3-di-n-propylamino-propyl amino, 4-diethylaminobutyl
amino, and 3-carboxypropionyl amino. R4 and RS can be taken together with the
nitrogen to which they are attached to form a ring having 3 to 7 carbon atoms
and
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l, 2, or 3 heteroatoms selected from the group consisting of nitrogen,
substituted
nitrogen, oxygen, and sulfur. Examples of such cyclic NR4R5 groups include
pyrrolidinyl, piperazinyl, 4-methylpiperazinyl, 4-benzylpiperazinyl,
pyridinyl,
piperidinyl, pyrazinyl, morpholinyl, and the like.
~ "Halo" includes fluoro, chloro, bromo, and iodo.
Examples of substituted alkyl groups include 2-aminoethyl,
pentachloroethyl, trifluoromethyl, 2-diethylaminoethyl, 2-dimethylaminopropyl,
ethoxycarbonylmethyl, 3-phenylbutyl, methanylsulfanylmethyl, methoxymethyl,
3-hydroxypentyl, 2-carboxybutyl, 4-chlorobutyl, 3-cyclopropylpropyl,
JO pentafluoroethyl, benzyl(Bn), 3-morpholinopropyl, piperazinylmethyl,
pyridyl-
4-methyl(Py-4-me), 3-(pyridyl-4-thio)propyl, and 2-(4-methylpiperazinyl)ethyl.
Examples of substituted alkynyl groups include 2-methoxyethynyl,
2-ethylsulfanyethynyl, 4-(1-piperazinyl)-3-(butynyl), 3-phenyl-5-hexynyl,
3-diethylamino-3-butynyl, 4-chloro-3-butynyl, 4-cyclobutyl-4-hexenyl, and the
like.
Typical substituted alkoxy groups include aminomethoxy,
trifluoromethoxy, 2-diethylaminoethoxy, 2-ethoxycarbonylethoxy,
3-hydroxypropoxy, 6-carboxhexyloxy, and the like.
Further, examples of substituted alkyl, alkenyl, and alkynyl groups include
dimethylaminomethyl, carboxymethyl, 4-dimethylamino-3-buten-1-yl,
5-ethylmethylamino-3-pentyn-1-yl, 4-morpholinobutyl,
4-tetrahydropyrinidylbutyl, 3-imidazolidin-J-ylpropyl, 4-tetrahydrothiazol-
3-yl-butyl, phenylmethyl, 3-chlorophenylmethyl, and the like.
The terms "Ar" and "aryl" refer to unsubstituted and substituted aromatic
groups. Heteroaryl groups have from 4 to 10 ring atoms, from 1 to 4 of which
are
independently selected from the group consisting of O, S, and N. Preferred
heteroaryl groups have 1 or 2 heteroatoms in a 5- or 6-membered aromatic ring.
Mono- and bicyclic aromatic ring systems are included in the definition of
aryl
and heteroaryl. Typical aryl and heteroaryl groups include phenyl, 3-
chlorophenyl,
3,4-methylenedioxyphenyl, 2,6-dibromophenyl, pyridyl, 3-methylpyridyl,
4-thiopyridyl, benzothienyl, 2,4,6-tribromophenyl, 4-ethylbenzothienyl,
furanyl,
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3,4-diethylfuranyl, naphthyl, 4,7-dichloronaphthyl, morpholinyl, indolyl,
benzotriazolyl, indazolyl, pyrrole, pyrazole, imidazole, thiazole, and the
like.
Preferred Ar groups are phenyl or naphthyl, and phenyl or naphthyl
substituted by l, 2, or 3 groups independently selected from the group
consisting
of alkyl, alkoxy, thio, thioalkyl, thioalkoxy, (CH2)mN(R4)S(O)2(Cl-C6 alkyl),
(CH2)mS(O)2NR4R5, wherein R4, R5, and m are as defined above,
S(O)2NR4R5, C(O)NR4R5, N(H)C(O)NR4R5, O-C(O)NR4R5, halo, hydroxy,
-COOR6, trif7uoromethyl, vitro, amino of the formula -NR4R5, C(O)NR4R5,
S(O)Cl-C6 alkyl, S(O)2C1-C6 alkyl, 5-membered heteroaryl,
N(RS)C(O)O(Cl-C6 alkyl), and T(CH2)pQR4 or T(CH2)pC02R4, wherein p is
1 to 6, T is O, S, SO, S02, NR4, N(O)R4, NR4R6Y, or CR4R5, Q is O, S, SO,
S02, NRS, N(O)R5, or NR5R6Y, wherein R4 and RS are as described above, Y is
a counter ion such as halo, R6 is H, Cl-C6 alkyl, or substituted C~-C6 alkyl,
for
example, methyl, trichloroethyl, diphenylmethyl, and the like. The alkyl and
alkoxy groups can be substituted as defined above. For example, typical groups
are carboxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, hydroxyalkoxy, and
alkoxyalkyl. Examples of substituted phenyl are 3-methoxyphenyl,
2,6-dichlorophenyl, 3-nitrophenyl, 4-dimethylaminophenyl, and biphenyl.
Examples of quaternary ammonium groups defined by NR4R6Y are
trimethylammonium chloride and triethylammonium bromide.
Heteroaryl groups may be substituted with up to 3 groups independently
selected from the l, 2, or 3 groups described above for substituted phenyl.
DEFINTTIONS OF TERMS USED TO DEFINE COMPOUNDS OF FORMULA
iF:
In Formula IF, Rl to R9 include "Cl-C6 alkyl" groups. These are straight
and branched carbon chains having from 1 to 6 carbon atoms. Examples of such
alkyl groups include methyl, ethyl, isopropyl, tert-butyl, neopentyl, and n-
hexyl.
The alkyl groups can be substituted if desired, for instance with groups such
as
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hydroxy, amino, alkyl, and dialkylamino, halo, trifluoromethyl, carboxy,
nitro,
and cyano.
"Alkenyl" means straight and branched hydrocarbon radicals having from
2 to 6 carbon atoms and one double bond and includes ethenyl, 3-buten-1-yl,
2-ethenylbutyl, 3-hexen-1-yl, and the like.
"Alkynyl" means straight and branched hydrocarbon radicals having from
2 to 6 carbon atoms and one triple bond and includes ethynyl, 3-butyn-1-yl,
propynyl, 2-butyn-1-yl, 3-pentyn-1-yl, and the like.
"Cycloalkyl" means a monocyclic or polycyclic hydrocarbyl group such as
cyclopropyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclobutyl, adamantyl,
norpinanyl, decalinyl, norbornyl, cyclohexyl, and cyclopentyl. Such groups can
be
substituted with groups such as hydroxy, keto, and the like. Also included are
rings in which 1 to 3 heteroatoms replace carbons. Such groups are termed
"heterocyclyl," which means a cycloalkyl group also bearing at least one
heferoatom selected from O, S, or NR2, examples being oxiranyl, pyrrolidinyl,
piperidyl, tetrahydropyranyl, and morpholinyl.
"Alkoxy" refers to the alkyl groups mentioned above bound through
oxygen, examples of which include methoxy, ethoxy, isopropoxy, tert-butoxy,
and
the like. In addition, alkoxy refers to polyethers such as -O-(CH2)2-O-OH3,
and
the like.
"Acyl" means an R group that is an alkyl or aryl (Ar) group bonded
through a carbonyl group, i.e., R-C(O)-, where R is alkyl or aryl. For
example,
acyl includes a C1-C6 alkanoyl, including substituted alkanoyl, wherein the
alkyl
portion can be substituted by NR4R5 or a carboxylic or heterocyclic group.
Typical acyl groups include acetyl, benzoyl, isonicotinoyl, and the like.
The alkyl, alkenyl, alkoxy, and alkynyl groups described above are
optionally substituted, preferably by 1 to 3 groups selected from NR4R5,
phenyl,
substituted phenyl, thio C1-C6 alkyl, C1-C6 alkoxy, hydroxy, carboxy, C1-C6
alkoxycarbonyl, acyl, halo, nitrile, cycloalkyl, and a 5- or 6-membered
carbocyclic ring or heterocyclic ring having 1 or 2 heteroatoms selected from
nitrogen, substituted nitrogen, oxygen, and sulfur. "Substituted nitrogen"
means
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nitrogen bearing C1-C6 alkyl or (CH2)nPh where ~n is l, 2, or 3. Perhalo and
polyhalo substitution is also embraced.
Examples of substituted alkyl groups include 2-aminoethyl, acetylmethyl,
pentachloroethyl, trifluoromethyl, 2-diethylaminoethyl, 2-dimethylaminopropyl,
ethoxycarbonylmethyl, 3-phenylbutyl, methanylsulfanylmethyl, methoxymethyl,
3-hydroxypentyl, 2-carboxybutyl, 4-chlorobutyl, 3-cyclopropylpropyl,
pentafluoroethyl, 3-morpholinopropyl, piperazinylmethyl, 4-benzoylbutyl, and
2-(4-methylpiperazinyl)ethyl.
Examples of substituted alkynyl groups include 2-methoxyethynyl,
2-benzoylethylyl, 2-ethylsulfanyethynyl, 4-(1-piperazinyl)-3-(butynyl), 3-
phenyl
5-hexynyl, 3-diethylamino-3-butynyl, 4-chloro-3-butynyl, 4-cyclobutyl
4-hexenyl, and the like.
Typical substituted alkoxy groups include aminomethoxy,
acetoxymethoxy, trifluoromethoxy, 2-diethylaminoethoxy,
2-ethoxycarbonylethoxy, 3-hydroxypropoxy, 6-carboxhexyloxy, and the like.
Further, examples of substituted alkyl, alkenyl, and alkynyl groups include
dimethylaminomethyl, carboxymethyl, 4-dimethylamino-3-buten-1-yl,
5-ethylmethylamino-3-pentyn-1-yl, 4-morpholinobutyl,
4-tetrahydropyrinidylbutyl, 3-imidazolidin-l-ylpropyl, 4-tetrahydrothiazol-
3-yl-butyl, phenylmethyl, 3-chlorophenylmethyl, and the like.
The terms "Ar" and "aryl" refer to unsubstituted and substituted aromatic
groups. Heteroaryl (Het) groups have from 4 to 9 ring atoms, from 1 to 4 ring
atoms of which are independently selected from the group consisting of O, S,
and N. Preferred heteroaryl groups have 1 or 2 heteroatoms in a 5- or 6-
membered
aromatic ring. Mono- and bicyclic aromatic ring systems are included in the
definition of aryl and heteroaryl. Preferred substituent groups include alkyl,
alkoxy, halo, amino, alkylamino, dialkylamino, CN, CF3, thioalkyl, acyl and
hydroxy. Typical aryl and heteroaryl groups include phenyl, 3-chlorophenyl,
2,6-dibromophenyl, pyridyl, 3-methylpyridyl, benzothienyl, 2,4,6-
tribromophenyl,
4-ethylbenzothienyl, furanyl, 3,4-diethylfuranyl, naphthyl, 4,7-
dichloronaphthyl,
morpholinyl, indolyl, benzotriazolyl, indazolyl, pyrrole, pyrazole, imidazole,
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thiazole, methylenedioxyphenyl, benzo-2,1,3-thiadiazole, benzo-2,1,3-
oxadiazole,
and the like.
Preferred Ar groups are phenyl and phenyl substituted by l, 2, or 3 groups
independently selected from the group consisting of alkyl, alkoxy, thio,
thioalkyl,
halo, hydroxy, -COORS, trifluoromethyl, vitro, amino of the formula -NR4R5,
and' T(CH2)mQR4 or T(CH2)mC02R4 wherein m is I to 6, T is O, S, NR4,
N(O)R4, NR4R6Y, or CR4R5, Q is O, S, NRS, N(O)R5, or NRSR6Y wherein
R4 and R5 are as described above, and R~ is hydrogen, alkyl, or substituted
alkyl,
for example, methyl, trichloroethyl, diphenylmethyl, and the like. The alkyl
and
alkoxy groups can be substituted as defined above. For example, typical groups
are carboxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, hydroxyalkoxy, and
alkoxyalkyl. Typical substituted aryl groups include 2,6-dichlorophenyl,
3-hydroxyphenyl, 1,3-benzodioxolyl, 4-dimethylaminophenyl,
2,4,6-triethoxyphenyl, 3-cyanophenyl, 4-methylthiophenyl, and 3,5-
dinitrophenyl.
Examples of NR4R5 groups include amino, methylamino,
di-isopropylamino, acetyl amino, propionyl amino, 3-aminopropyl amino,
3-ethylaminobutyl amino, 3-di-n-propylamino-propyl amino, 4-diethylaminobutyl
amino, and 3-carboxypropionyl amino. R4 and RS can be taken together with the
nitrogen to which they are attached to form a ring having 3 to 7 carbon atoms
and
1, 2, or 3 heteroatoms selected from the group consisting of nitrogen,
substituted
nitrogen, oxygen, and sulfur. Examples of such cyclic NR4R5 groups include
pyrrolidinyl, piperazinyl, 4-methylpiperazinyl, 4-benzylpiperazinyl,
pyridinyl,
piperidinyl, pyrazinyl, morpholinyl, and the like.
"Halo" includes fluoro, chloro, bromo, and iodo.
DEFINITIONS OF TERMS USED TO DEFINE COMPOUNDS OF FORMULA
IG:
In Formula IG, R1 to R9 include "C1-C6 alkyl" groups. These are straight
and branched carbon chains having from 1 to 6 carbon atoms. Examples of such
alkyl groups include methyl, ethyl, isopropyl, tert-butyl, neopentyl, and n-
hexyl.
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The alkyl groups can be substituted if desired, for instance with groups such
as
hydroxy, amino, alkyl, aryl, and dialkylamino, halo, trifluoromethyl, carboxy,
nitro, and cyano.
"Alkenyl" means straight and branched hydrocarbon radicals having from
2 to 6 carbon atoms and one double bond and includes ethenyl, 3-buten-1-yl,
2-ethenylbutyl, 3-hexen-1-yl, and the like.
"Alkynyl" means straight and branched hydrocarbon radicals having from
2 to 6 carbon atoms and one triple bond and includes ethynyl, 3-butyn-1-yl,
propynyl, 2-butyn-1-yl, 3-pentyn-1-yl, and the like.
"Cycloalkyl" means a monocyclic or polycyclic hydrocarbyl group such as
cyclopropyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclobutyl, adamantyl,
norpinanyl, decalinyl, norbornyl, cyclohexyl, and cyclopentyl. Such groups can
be
substituted with groups such as hydroxy, keto, and the like. Cycloalkyl groups
can also be fused by two points of attachment to other groups such as aryl and
heteroaryl groups. Also included are rings in which 1 to 3 heteroatoms replace
carbons. Such groups are termed "heterocyclyl," which means a cycloalkyl group
also bearing at least one heteroatom selected from O, S, or NR2, examples
being
oxiranyl, pyrrolidinyl, piperidyl, tetrahydropyran, and morpholine.
"Alkoxy" refers to the alkyl groups mentioned above bound through
oxygen, examples of which include methoxy, ethoxy, isopropoxy, tert-butoxy,
and
the like. In addition, alkoxy refers to polyethers such as -O-(CH2)2-O-OH3,
and
the like.
"Acyl" means an R group that is an alkyl or aryl (Ar) group bonded
through a carbonyl group, i.e., R-C(O)-, where R is alkyl or aryl. For
example,
acyl includes a C1-C6 alkanoyl, including substituted alkanoyl, wherein the
alkyl
portion can be substituted by NR4R5 or a carboxylic or heterocyclic group.
Typical acyl groups include acetyl, benzoyl, isonicotinoyl, and the like.
The alkyl, alkenyl, alkoxy, and alkynyl groups described above are
optionally substituted, preferably by 1 to 3 groups selected from NR4R5,
phenyl,
substituted phenyl, naphthyl, thio C1-C6 alkyl, C1-C6 alkoxy, hydroxy,
carboxy,
C1-C6 alkoxycarbonyl, acyl, halo, nitrile, cycloalkyl, and a 5- or 6-membered
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carbocyclic ring or heterocyclic ring having 1 or 2 heteroatoms selected from
nitrogen, substituted nitrogen, oxygen, and sulfur. "Substituted nitrogen"
means
nitrogen bearing Cl-C6 alkyl or (CH2)nPh where n is 1, 2, or 3. Perhalo and
polyhalo substitution is also embraced.
~ Examples of substituted alkyl groups include 2-aminoethyl, acetylmethyl,
pentachloroethyl, trif7uoromethyl, 2-diethylaminoethyl, 2-dimethylaminopropyl,
ethoxycarbonylmethyl, 3-phenylbutyl, methanylsulfanylmethyl, methoxymethyl,
3-hydroxypentyl, 2-carboxybutyl, 4-chlorobutyl, 3-cyclopropylpropyl,
pentaf7uoroethyl, 3-morpholinopropyl, piperazinylmethyl, 4-benzoylbutyl, and
2-(4-methylpiperazinyl)ethyl.
Examples of substituted alkynyl groups include 2-methoxyethynyl,
2-benzoylethylyl, 2-ethylsulfanyethynyl, 4-(1-piperazinyl)-3-(butynyl), 3-
phenyl-
5-hexynyl, 3-diethylamino-3-butynyl, 4-chloro-3-butynyl, 4-cyclobutyl-
4-hexenyl, and the like.
Typical substituted alkoxy groups include aminomethoxy,
acetoxymethoxy, trifluoromethoxy, 2-diethylaminoethoxy,
2-ethoxycarbonylethoxy, 3-hydroxypropoxy, 6-carboxhexyloxy, and the like.
Further, examples of substituted alkyl, alkenyl, and alkynyl groups include
dimethylaminomethyl, carboxymethyl, 4-dimethylamino-3-buten-1-yl,
5-ethylmethylamino-3-pentyn-1-yl, 4-morpholinobutyl,
4-tetrahydropyrinidylbutyl, 3-imidazolidin-1-ylpropyl, 4-tetrahydrothiazol-
3-yl-butyl, phenylmethyl, 3-chlorophenylmethyl, and the like.
The terms "Ar" and "aryl" refer to unsubstituted and substituted aromatic
groups. Heteroaryl (Het) groups have from 4 to 9 ring atoms, from 1 to 4 of
which
are independently selected from the group consisting of O, S, and N. Preferred
heteroaryl groups have 1 or 2 heteroatoms in a 5- or 6-membered aromatic ring.
Mono- and bicyclic aromatic ring systems are included in the definition of
aryl
'and heteroaryl. Preferred substituent groups include alkyl, alkoxy, aryloxy,
halo,
amino, alkylamino, dialkylamino, CN, CF3, thioalkyl, acyl and hydroxy. Typical
aryl and heteroaryl groups include phenyl, 3-chlorophenyl, 2,6-dibromophenyl,
pyridyl, 3-methylpyridyl, benzothienyl, 2,4,6-tribromophenyl,
4-ethylbenzothienyl, furanyl, 3,4-diethylfuranyl, naphthyl, 4,7-
dichloronaphthyl,
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morpholinyl, indolyl, benzotriazolyl, indazolyl, pyrrole, pyrazole, imidazole,
thiazole, methylenedioxyphenyl, benzo-2,1,3-thiadiazole, benzo-2,1,3-
oxadiazole,
and the like.
Preferred Ar groups are phenyl and phenyl substituted by 1, 2, or 3 groups
independently selected from the group consisting of alkyl, alkoxy, thio,
thioalkyl,
halo, hydroxy, -COORS, trifluoromethyl, nitro, amino of the formula -NR4R5,
and T(CH2)mQR4 or T(CH2)mC02R4 wherein m is 1 to 6, T is O, S, NR4,
N(O)R4, NR4R6Y, or CR4R5, Q is O, S, NRS, N(O)R5, or NR5R6Y wherein
R4 and R5 are as described above, and R~ is hydrogen, alkyl, or substituted
alkyl,
for example, methyl, trichloroethyl, diphenylmethyl, and the like. The alkyl
and
alkoxy groups can be substituted as defined above. For example, typical groups
are carboxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, hydroxyalkoxy, and
alkoxyalkyl. Typical substituted aryl groups include 2,6-dichlorophenyl,
3-hydroxyphenyl, 1,3-benzodioxolyl, 4-dimethylaminophenyl,
2,4,6-triethoxyphenyl, 3-cyanophenyl, 4-methylthiophenyl, and 3,5-
dinitrophenyl.
Examples of NR4R5 groups include amino, methylamino,
di-isopropylamino, acetyl amino, propionyl amino, 3-aminopropyl amino,
3-ethylaminobutyl amino, 3-di-n-propylamino-propyl amino, 4-diethylaminobutyl
amino, and 3-carboxypropionyl amino. R4 and RS can be taken together with the
nitrogen to which they are attached to form a ring having 3 to 7 carbon atoms
and
l, 2, or 3 heteroatoms selected from the group consisting of nitrogen,
substituted
nitrogen, oxygen, and sulfur. Examples of such cyclic NR4R5 groups include
pyrrolidinyl, piperazinyl, 4-methylpiperazinyl, 4-benzylpiperazinyl,
pyridinyl,
piperidinyl, pyrazinyl, morpholinyl, and the like.
"Halo" includes fluoro, chloro, bromo, and iodo.
Unless moieties of a compound of the invention are defined as being
unsubstituted, the moieties of the compound of the invention may be
substituted.
In the event where the substituents of the moieties which may be substituted
are
not defined above, the moieties of the compound of the invention may be
optionally substituted from 1 to 3 times at any of from 1 to 3 carbon atoms,
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respectively, wherein each carbon atom is capable of substitution by
replacement
of a hydrogen atom with a group independently selected from:
C~-C4 alkyl;
Cz-C4 alkenyl;
' Cz-C4 alkynyl;
CFs
halo;
OH;
O-(C~-C4 alkyl);
OCH2F;
OCHFz;
OCF3;
OC(O)-(C~-C4 alkyl);
OC(O)O-(C~-C4 alkyl);
~ OC(O)NH-(C~-C4 alkyl);
OC(O)N(C~-C4 alkyl)z;
OC(S)NH-(C~-C4 alkyl);
OC(S)N(C~-C4 alkyl)z;
SH;
S-(C~-C4 alkyl);
S(O)-(C~-C4 alkyl);
S(O)z-(C~-C4 alkyl);
SC(O)-(C,-C4 alkyl);
SC(O)O-(C~-C4 alkyl);
NHz
N(H)-(C~-C4 alkyl);
N(C~-C4 alkyl)z;
N(H)C(O)-(C~-C4 alkyl);
N(CH3)C(O)-(C~-C4 alkyl);
N(H)C(O)-CF3;
N(CH3)C(O)-CF3;
N(H)C(S)-(C~-C4 alkyl);
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N(CH3)C(S)-(C~-C4 alkyl);
N(H)S(O)2-(C,-C4 alkyl);
N(H)C(O)NH2;
N(H)C(O)NH-(C~-C4 alkyl);
N(CH3)C(O)NH-(C~-C4 alkyl);
N(H)C(O)N(C~-C4 alkyl)2;
N(CH3)C(O)N(C~-C4 alkyl)2;
N(H)S(O)2NH2;
N(H)S(O)2NH-(C,-C4 alkyl);
N(CH3)S(O)2NH-(C,-C4 alkyl);
N(H)S(O)2N(C~-C4 alkyl)2;
N(CH3)S(O)2N(C~-C4 alkyl)2;
N(H)C(O)O-(C,-C4 alkyl);
N(CH3)C(O)O-(C~-C4 alkyl);
N(H)S(O)20-(C~-C4 alkyl);
N(CH3)S(O)20-(C~-C4 alkyl);
N(CH3)C(S)NH-(C~-C4 alkyl);
N(CH3)C(S)N(C~-C4 alkyl)2;
N(CH3)C(S)O-(C~-C4 alkyl);
N(H)C(S)NH2;
NO2;
C02H;
COZ-(C~-C4 alkyl);
C(O)N(H)OH;
C(O)N(CH3)OH;
C(O)N(CH3)OH;
C(O)N(CH3)O-(C~-C4 alkyl);
C(O)N(H)-(C~-C4 alkyl);
C(O)N(C~-C4 alkyl)2;
C(S)N(H)-(C~-C4 alkyl);
C(S)N(C~-C4 alkyl)2;
C(NH)N(H)-(C~-C4 alkyl);
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C(NH)N(C~-C4 alkyl)2;
C(NCH3)N(H)-(C~-C4 alkyl);
C(NCH3)N(C~-C4 alkyl)z;
C(O)-(C~-C4 alkyl);
' C(NH)-(C~-C4 alkyl);
C(NCH3)-(C~-C4 alkyl);
C(NOH)-(C~-C4 alkyl);
C(NOCH3)-(C~-C4 alkyl);
CN;
CHO;
CH20H;
CHZO-(C~-C4 alkyl);
CHZNH2;
CHZN(H)-(C~-C4 alkyl); and
' CHZN(C~-C4 alkyl)2; wherein
"C,-Ca alkyl" means a straight or branched, unsubstituted alkyl chain of from
1 to
4 carbon atoms;
"C2-C4 alkenyl" means a straight or branched, unsubstituted alkenyl chain of
from
2 to 4 carbon atoms; and
"CZ-C4 alkynyl" means a straight or branched, unsubstituted alkynyl chain of
from
2 to 4 carbon atoms.
It should be appreciated that the S 1' site of MMP-13 was previously
thought to be a grossly linear channel which contained an opening at the top
that
allowed an amino acid side chain from a substrate molecule to enter during
binding, and was closed at the bottom. Applicant has discovered that the Sl'
site is
actually composed of an Sl' channel angularly connected to a newly discovered
pocket which applicant calls the Sl" site. The S1" site is open to solvent at
the
bottom, which can expose a functional group of Applicant's allosteric
carboxylic
inhibitors to solvent. For illustrative purposes, the S 1' site of the MMP-13
enzyme
can now be thought of as being like a sock with a hole in the toes, wherein
the S 1'
channel is the region from approximately the opening to the ankle, and the Sl"
site
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is the foot region below the ankle, which foot region is angularly connected
to the
ankle region.
More particularly, the Sl' channel is a specific part of the S1' site and is
formed largely by Leu218, Va1219, His222 and by residues from Leu239 to
Tyr244. The Sl" binding site which has been newly discovered is defined by
residues from Tyr246 to Pro255. The Sl" site contains at least two hydrogen
bond
donors and aromatic groups which interact with a compound which is an
allosteric
carboxylic inhibitor of MMP-13.
Without wishing to be bound by any particular theory, the inventor
believes that the S1" site could be a recognition site for triple helix
collagen, the
natural substrate for MMP-13. It is possible that the conformation of the S1"
site is
modified only when an appropriate compound binds to MMP-13, thereby
interfering with the collagen recognition process. This newly discovered
pattern of
binding offers the possibility of greater selectivity than what is achievable
with the
binding pattern of known selective inhibitors of MMP-13, wherein the known
binding pattern requires ligation of the catalytic zinc atom at the active
site and
occupation the Sl' channel, but not the S1" site.
The instant allosteric carboxylic inhibitors of MMP-13 are described in co-
pending PCT international applications and their corresponding United States
nonprovisional application numbers 10/071,032; 10/075,918; 10/075,073;
10/075,069; 10/075,954; 10/075,654; 10/074,646; 10/075,909; and 10/071,073,
and the related United States provisional application numbers 60/268,780;
60/268,736; 60/268,756; 60/268,821; 60/268,861; 60/268,757; 60/268,782;
60/268,779; and 60/268,781, respectively, all provisional applications filed
on
February 14, 2001, and from which benefit of priority is claimed. All of the
these
PCT International applications, United States provisional applications, and
United
States nonprovisional applications are incorporated herein by reference. For
convenience, the allosteric inhibitors of MMP-13 patent application filing
information is listed below in Table A.
Table A: Allosteric inhibitors of MMP-13 patent application filing information
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Corresponding
U.S. ProvisionalU.S. ProvisionalU.S. Corresponding
NonprovisionalPCT International
Application Application Application Application
Number Filing Date Number Number
60/268,780 February 14, 10/071,032 PCT/IB02/00313
2001
60/268,736 February 14, 10/075,918 PCT/IB02/00344
2001
60/268,756 February 14, 10/075,073 PCT/IB02/00204
2001
60/268,821 February 14, 10/075,069 PCT/IB02/00447
2001
60/268,661 February 14, 10/075,954 PCT/EP02/01979
2001
60/268,757 February 14, 10/075,654 PCT/FR02/00504
2001
60/268,782 February 14, 10/074,646 PCT/IB02/00083
2001
60/268,779 February 14, 10/075,909 PCT/IB02/00190
2001
60/268,781 February 14, 10/071,073 PCT/IB02/00345
2001
It should be appreciated that invention combinations may comprise
celecoxib, or a pharmaceutically acceptable salt thereof, or valdecoxib, or a
pharmaceutically acceptable salt thereof, and an allosteric carboxylic
inhibitor of
MMP-l 3, or a pharmaceutically acceptable salt thereof, wherein the allosteric
carboxylic inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof,
may embrace any one of the compound embodiments described in co-pending
PCT international applications and their corresponding United States
nonprovisional application numbers 10/071,032; 10/075,918; 10/075,073;
10/075,069; 10/075,954; 10/075,654; 10/074,646; 10/075,909; and 10/071,073,
and the related United States provisional application numbers 60/268,780;
60/268,736; 60/268,756; 60/268,821; 60/268,861; 60/268,757; 60/268,782;
60/268,779; and 60/268,781, respectively, including variants thereof described
in
the respective specifications and claims. It should be further appreciated
that the
above-described pharmaceutical compositions may comprise these invention
combinations. It should be further appreciated that the above described
methods of
prevention, treatment, or inhibition may comprise administration of these
invention combinations.
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A compound that is an allosteric carboxylic inhibitor of MMP-13 may be
readily identified by one of ordinary skill in the pharmaceutical or medical
arts by
assaying an carboxylic test compound for inhibition of MMP-13 as described
below in Biological Methods 1 or 2, and for allosteric inhibition of MMP-13 by
assaying the carboxylic test compound for inhibition of MMP-13 in the presence
of an inhibitor to the catalytic zinc of MMP-13 as described below in
Biological
Methods 3 or 4.
Further, an allosteric carboxylic inhibitor of MMP-13 having an anti-
inflammatory, an analgesic, anti-arthritic, or a cartilage damage inhibiting
effect,
or any combination of these effects, may be readily identified by one of
ordinary
skill in the pharmaceutical or medical arts by assaying the allosteric
carboxylic
inhibitor of MMP-13 in any number of well known assays for measuring
determining the allosteric carboxylic inhibitor of MMP-13's effects on
cartilage
damage, arthritis, inflammation, or pain. These assays include in vitro assays
that
utilize cartilage samples and in vivo assays in whole animals that measure
cartilage degradation, inhibition of inflammation, or pain alleviation.
For example with regard to assaying cartilage damage in vitro, an amount
of an allosteric carboxylic inhibitor of MMP-13 or control vehicle may be
administered with a cartilage damaging agent to cartilage, and the cartilage
damage inhibiting effects in both tests studied by gross examination or
histopathologic examination of the cartilage, or by measurement of biological
markers of cartilage damage such as, for example, proteoglycan content or
hydroxyproline content. Further, in vivo assays to assay cartilage damage may
be
performed as follows: an amount of an allosteric carboxylic inhibitor of MMP-
13
or control vehicle may be administered with a cartilage damaging agent to an
animal, and the effects of the allosteric carboxylic inhibitor of MMP-13 being
assayed on cartilage in the animal may be evaluated by gross examination or
histopathologic examination of the cartilage, by observation of the effects in
an
acute model on functional limitations of the affected joint that result from
cartilage damage, or by measurement of biological markers of cartilage damage
such as, for example, proteoglycan content or hydroxyproline content. Several
methods of identifying an allosteric carboxylic inhibitor of MMP-13 with
cartilage
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damage inhibiting properties are described below. The amount to be
administered
in an assay to identify an allosteric carboxylic inhibitor of MMP-13 is
dependent
upon the particular assay employed, but in any event is not higher than the
well
known maximum amount of a compound that the particular assay can effectively
accommodate.
Similarly, allosteric carboxylic inhibitors of MMP-13 having pain-
alleviating properties may be identified using any one of a number of in vivo
animal models of pain.
Still similarly, allosteric carboxylic inhibitors of MMP-13 having anti-
inflammatory properties may be identified using any one of a number of in vivo
animal models of inflammation. For example, for an example of inflammation
models, see United States patent number 6, 329,429, which is incorporated
herein
by reference.
Still similarly, allosteric carboxylic inhibitors of MMP-13 having anti-
arthritic properties may be identified using any one of a number of in vivo
animal
models of arthritis. For example, for an example of arthritis models, see also
United States patent number 6, 329,429.
Any allosteric carboxylic inhibitor of MMP-13 is readily available, either
commercially, or by synthetic methodology, well known to those skilled in the
art
of organic chemistry. For specific syntheses, see the examples below and the
preparations of allosteric carboxylic inhibitors of MMP-13 described in the
above-
referenced patent applications.
The term "celecoxib" means the compound named 4-(5-(4-methylphenyl)-
3-(trifluoromethyl)-1H-pyrazol-1-yl)-benzenesulfonamide. Celecoxib is
currently
approved by the FDA for the treatment of osteoarthritis, rheumatoid arthritis,
and
Polyposis-familial adenomatus. Celecoxib is marketed under the tradename
"Celebrex". Celecoxib is currently in clinical trials for the treatment of
bladder
cancer, chemopreventative-lung cancer, and post-operative pain, and is
registered
for the treatment of dysmenorrhea. Celecoxib has the structure drawn below:
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O CF3
O' (S / \ N Nw
H2N
r
H3C
It should be appreciated that the invention combination may include
celecoxib, or a pharmaceutically acceptable salt thereof. Preferred invention
combinations include celecoxib.
The term "valdecoxib" means the compound named 4-(5-methyl-3-phenyl-
4-isoxazolyl)-benzenesulfonamide. Valdecoxib has been approved by the FDA for
treating osteoarthritis, rheumatoid arthritis, dysmenorrhea, and general pain,
and is
marketed under the tradename "Bextra". Valdecoxib is in clinical trials for
the
treatment of migraine. Valdecoxib has the structure drawn below:
H
NH2
It should be appreciated that the invention combination may include
valdecoxib, or a pharmaceutically acceptable salt thereof. Preferred invention
combinations include valdecoxib.
It should be further appreciated that celecoxib and valdecoxib are each
selective inhibitors of COX-2, which is also known as prostaglandin synthase-2
and prostaglandin PGHZ synthase.
A selective inhibitor of COX-2 means compounds that inhibit COX-2
selectively versus COX-1 such that a ratio of ICSO for a compound with COX-1
divided by a ratio of ICSO for the compound with COX-2 is greater than, or
equal
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to, 5, where the ratios are determined in one or more of the in vitro, in
vivo, or ex
vivo assays described below. All that is required to determine whether a
compound is a selective COX-2 inhibitor is to assay a compound in one of the
pairs of assays described in Biological Methods 5 to 8 below. Preferred
selective
COX-2 inhibitors have a selectivity greater than 5 fold versus COX-1 in the
assay
described in Biological Method 5 below.
The term "NSAID" is an acronym for the phrase "nonsteroidal anti-
inflammatory drug", which means any compound which inhibits cyclooxygenase-
1 ("COX-1 ") and cyclooxygenase-2. Most NSAIDs fall within one of the
following five structural classes: (1) propionic acid derivatives, such as
ibuprofen,
naproxen, naprosyn, diclofenac, and ketoprofen; (2) acetic acid derivatives,
such
as tolmetin and sulindac; (3) fenamic acid derivatives, such as mefenamic acid
and meclofenamic acid; (4) biphenylcarboxylic acid derivatives, such as
diflunisal
and flufenisal; and (5) oxicams, such as piroxim, peroxicam, sudoxicam, and
isoxicam. Other useful NSAIDs include aspirin, acetaminophen, indomethacin,
and phenylbutazone. Selective inhibitors of cyclooxygenase-2 as described
above
may be considered to be NSAIDs also.
For the purposes of this invention, the term "arthritis", which is
synonymous with the phrase "arthritic condition", includes osteoarthritis,
rheumatoid arthritis, degenerative joint disease, spondyloarthropathies, gouty
arthritis, systemic lupus erythematosus, juvenile arthritis, and psoriatic
arthritis.
An allosteric carboxylic inhibitor of MMP-13 having an anti-arthritic effect
is a
compound as defined above that inhibits the progress, prevents further
progress,
or reverses progression, in part or in whole, of any one or more symptoms of
any
one of the arthritic diseases and disorders listed above.
Other mammalian diseases and disorders which are treatable by
administration of an invention combination alone, or contained in a
pharmaceutical composition as defined below, include: fever (including
rheumatic
fever and fever associated with influenza and other viral infections), common
cold,
dysmenorrhea, menstrual cramps, inflammatory bowel disease, Crohn's disease,
emphysema, acute respiratory distress syndrome, asthma, bronchitis, chronic
obstructive pulmonary disease, Alzheimer's disease, organ transplant toxicity,
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cachexia, allergic reactions, allergic contact hypersensitivity, cancer (such
as solid
tumor cancer including colon cancer, breast cancer, lung cancer and prostrate
cancer; hematopoietic malignancies including leukemias and lymphomas;
Hodgkin's disease; aplastic anemia, skin cancer and familiar adenomatous
polyposis), tissue ulceration, peptic ulcers, gastritis, regional enteritis,
ulcerative
colitis, diverticulitis, recurrent gastrointestinal lesion, gastrointestinal
bleeding,
coagulation, anemia, synovitis, gout, ankylosing spondylitis, restenosis,
periodontal
disease, epidermolysis bullosa, osteoporosis, loosening of artificial joint
implants,
atherosclerosis (including atherosclerotic plaque rupture), aortic aneurysm
(including abdominal aortic aneurysm and brain aortic aneurysm), periarteritis
nodosa, congestive heart failure, myocardial infarction, stroke, cerebral
ischemia,
head trauma, spinal cord injury, neuralgia, neuro-degenerative disorders
(acute and
chronic), autoimmune disorders, Huntington's disease, Parkinson's disease,
migraine, depression, peripheral neuropathy, pain (including low back and neck
pain, headache and toothache), gingivitis, cerebral amyloid angiopathy,
nootropic or
cognition enhancement, amyotrophic lateral sclerosis, multiple sclerosis,
ocular
angiogenesis, corneal injury, macular degeneration, conjunctivitis, abnormal
wound
healing, muscle or joint sprains or strains, tendonitis, skin disorders (such
as
psoriasis, eczema, scleroderma and dermatitis), myasthenia gravis,
polymyositis,
myositis, bursitis, burns, diabetes (including types I and II diabetes,
diabetic
retinopathy, neuropathy and nephropathy), tumor invasion, tumor growth, tumor
metastasis, corneal scarring, scleritis, immunodeficiency diseases (such as
AIDS in
humans and FLV, FN in cats), sepsis, premature labor, hypoprothrombinemia,
hemophilia, thyroiditis, sarcoidosis, Behcet's syndrome, hypersensitivity,
kidney
disease, Rickettsial infections (such as Lyme disease, Erlichiosis), Protozoan
diseases (such as malaria, giardia, coccidia), reproductive disorders
(preferably in
livestock), epilepsy, convulsions, and septic shock.
The term "Thr245" means threonine 245 of an MMP-13 enzyme.
The term "Thr247" means threonine 247 of an MMP-13 enzyme.
The term "Met253" means methionine 253 of an MMP-13 enzyme.
The term "His251" means histidine 251 of an MMP-13 enzyme.
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It should be appreciated that the matrix metalloproteinases include, but are
not limited to, the following enzymes:
MMP-l, also known as interstitial collagenase, collagenase-1, or
fibroblast-type collagenase;
' MMP-2, also known as gelatinase A or 72 kDa Type IV collagenase;
MMP-3, also known as stromelysin or stromelysin-l;
MMP-7, also known as matrilysin or PUMP-1;
MMP-8, also known as collagenase-2, neutrophil collagenase or
polymorphonuclear-type ("PMN-type") collagenase;
MMP-9, also known as gelatinase B or 92 kDa Type IV collagenase;
MMP-10, also known as stromelysin-2;
MMP-1 l, also known as stromelysin-3;
MMP-12, also known as metalloelastase;
MMP-13, also known as collagenase-3;
MMP-14, also known as membrane-type ("MT") 1-MMP or MT1-MMP;
MMP-15, also known as MT2-MMP;
MMP-16, also known as MT3-MMP;
MMP-17, also known as MT4-MMP;
MMP-18; and
MMP-19.
Other known MMPs include MMP-26 (Matrilysin-2).
The invention provides combinations which comprise an "allosteric
carboxylic inhibitor of MMP-l3". An allosteric carboxylic inhibitor of MMP-13
is
any compound that contains a carboxylic ester linker [i.e., -C(O)-O-C or C-O-
C(O)-] or
I I
carboxylic amide linker [i.e., -C(O)-N-C or C-N-C(O)-] and that binds to,
coordinates to, or ligates a site in an MMP-l3 enzyme that is at a location
other than
the enzyme's catalytically active site, wherein the catalytically active site
is the site
where the catalytic zinc canon of the MMP-13 enzyme binds, ligates, or
coordinates
a natural substrate(s). Thus an allosteric carboxylic inhibitor of MMP-13 is
any
carboxylic-containing inhibitor of an MMP-13 that does not bind to, coordinate
to,
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or ligate, either directly or indirectly via a bridging water molecule, the
catalytic
zinc cation of a MMP-13.
Further, an allosteric carboxylic inhibitor of MMP-13, as used in the
present invention, is a compound that does not ligate, coordinate to, or bind
to the
catalytic zinc cation of MMP-13, or a truncated form thereof, and is >_5 times
more potent in vitro versus MMP-13, or a truncated form thereof, than versus
at
least 2 other matrix metalloproteinase enzymes, including MMP-l, MMP-2,
MMP-3, MMP-7, MMP-8, MMP-9, MMP-10, MMP-11, MMP-l2, MMP-14,
MMP-17, MMP-18, MMP-19, MMP-21, and MMP-26, and tumor necrosis factor
alpha convertase ("TACE"). A preferred aspect of the present invention is
combinations comprising allosteric carboxylic inhibitors of MMP-13 that are
selective inhibitors of MMP-13 over MMP-1.
Other aspects of the present invention are allosteric carboxylic inhibitors
of MMP-13, or a pharmaceutically acceptable salt thereof, that are ?10, >_20,
?50,
>_100, or ?1000 times more potent versus MMP-13 than versus at least two of
any
other MMP enzyme or TACE.
Still other aspects of the present invention are allosteric carboxylic
inhibitors of MMP-I 3, or a pharmaceutically acceptable salt thereof, that are
selective inhibitors of MMP-13 versus 2, 3, 4, 5, 6, or 7 other MMP enzymes,
or
versus TACE and l, 2, 3, 4, 5, 6, or 7 other MMP enzymes.
It should be appreciated that selectivity of an allosteric carboxylic
inhibitor
of MMP-13, or a pharmaceutically acceptable salt thereof, is a
multidimensional
characteristic that includes the number of other MMP enzymes and TACE over
which selectivity for MMP-13 inhibition is present and the degree of
selectivity of
inhibition of MMP-l3 over another particular MMP or TACE, as measured by, for
example, the ICSO in micromolar concentration of inhibitor for the inhibition
of the
other MMP enzyme or TACE divided by the ICSO in micromolar concentration of
inhibitor for the inhibition of MMP-13
The term "ICSO" means the concentration of a compound, usually expressed
as micromolar or nanomolar, required to inhibit an enzyme's catalytic activity
by
50%.
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The term "ED4o" means the concentration of a compound, usually expressed
as micromolar or nanomolar, required to treat a disease in about 40% of a
patient
group.
The term "ED3o" means the concentration of a compound, usually expressed
as micromolar or nanomolar, required to treat a disease in 30% of a patient
group.
The phrase "pharmaceutical composition" means a composition suitable
for administration in medical or veterinary use.
The term "admixed" and the phrase "in admixture" are synonymous and
mean in a state of being in a homogeneous or heterogeneous mixture. Preferred
is
a homogeneous mixture.
As used herein, the phrase "cartilage damage" means a disorder of hyaline
cartilage and subchondral bone characterized by hypertrophy of tissues in and
around the involved joints, which may or may not be accompanied by
deterioration of hyaline cartilage surface.
l5 ~ The phrase "treating", which is related to the terms "treat" and
"treated",
means administration of an invention combination as defined above that
inhibits
the progress, prevents further progress, or reverses progression, in part or
in
whole, of any one or more symptoms of any one of the diseases and disorders
listed above.
The term "comprising," which is synonymous with the terms "including,"
"containing," or "characterized by," is inclusive or open-ended, and does not
exclude additional, unrecited elements or method steps from the scope of the
invention that is described following the term.
The phrase "consisting of " is closed-ended, and excludes any element,
step, or ingredient not specified in the description of the invention that
follows the
phrase.
The phrase "consisting essentially ofi' limits the scope of the invention that
follows to the specified elements, steps, or ingredients, and those further
elements,
steps, or ingredients that do not materially affect the basic and novel
characteristics of the invention.
The invention combination also includes isotopically-labelled compounds,
which are identical to those recited above, but for the fact that one or more
atoms
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are replaced by an atom having an atomic mass or mass number different from
the
atomic mass or mass number usually found in nature. Examples of isotopes that
can be incorporated into compounds of the invention include isotopes of
hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such
as
2H, 3H,'3C,'4C,'SN,'g0,'~O, 3'p, 32p, 35S, ~gF and 36C1, respectively.
Compounds
of the present invention and pharmaceutically acceptable salts of said
compounds
which contain the aforementioned isotopes and/or other isotopes of other atoms
are within the scope of this invention. Certain isotopically labelled
compounds of
the present invention, for example those into which radioactive isotopes such
as
3H and '4C are incorporated, are useful in drug and/or substrate tissue
distribution
assays. Tritiated, i.e., 3H and carbon-14, i.e.,'4C, isotopes are particularly
preferred for their ease of preparation and detectability. Further,
substitution with
heavier isotopes such as deuterium, i.e., 2H, can afford certain therapeutic
advantages resulting from greater metabolic stability, for example increased
in
vivo half-life or reduced dosage requirements and, hence, may be preferred in
some circumstances. Isotopically labelled compounds of those described above
in
this invention can generally be prepared by carrying out the procedures
incorporated by reference above or disclosed in the Schemes and/or in the
Examples and Preparations below, by substituting a readily available
isotopically
labelled reagent for a non-isotopically labelled reagent.
One of ordinary skill in the art will appreciate that the combinations of the
invention are useful in treating a diverse array of diseases. One of ordinary
skill in
the art will also appreciate that when using the combinations of the invention
in
the treatment of a specific disease that the combinations of the invention may
be
combined with various existing therapeutic agents used for that disease.
For the treatment of rheumatoid arthritis, the combinations of the invention
may be combined with agents such as TNF-a inhibitors such as anti-TNF
monoclonal antibodies and TNF receptor immunoglobulin molecules (such as
Enbrel~), low dose methotrexate, lefunimide, hydroxychloroquine, d-
penicilamine, auranofin or parenteral or oral gold.
The combinations of the invention can also be used in combination with
existing therapeutic agents for the treatment of osteoarthritis. Suitable
agents to
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be used in combination include standard non-steroidal anti-inflammatory agents
(hereinafter NSAID's) such as piroxicam, diclofenac, propionic acids such as
naproxen, flurbiprofen, fenoprofen, ketoprofen and ibuprofen, fenamates such
as
mefenamic acid, indomethacin, sulindac, apazone, pyrazolones such as
phenylbutazone, salicylates such as aspirin, COX-2 inhibitors such as
celecoxib
and, rofecoxib, analgesics and intraarticular therapies such as
corticosteroids and
hyaluronic acids such as hyalgan and synvisc.
This invention also relates to a method of or a pharmaceutical composition
for treating inflammatory processes and diseases comprising administering a
l0 combination of this invention to a mammal, including a human, cat,
livestock or
dog, wherein said inflammatory processes and diseases are defined as above and
said inhibitory combination is used in combination with one or more other
therapeutically active agents under the following conditions:
A.) where a joint has become seriously inflamed as well as infected at
the same time by bacteria, fungi, protozoa and/or virus, said inhibitory
combination is administered in combination with one or more antibiotic,
antifungal, antiprotozoal and/or antiviral therapeutic agents;
B.) where a multi-fold treatment of pain and inflammation is desired,
said inhibitory combination is administered in combination with inhibitors of
other mediators of inflammation, comprising one or more members independently
selected from the group consisting essentially of:
(1) NSAIDs;
(2) H~ -receptor antagonists;
(3) kinin-B~ - and BZ-receptor antagonists;
(4) prostaglandin inhibitors selected from the group consisting of PGD-,
PGF- PGI2 - and PGE-receptor antagonists;
(5) thromboxane AZ (TXA2-) inhibitors;
(6) 5-, 12- and 15-lipoxygenase inhibitors;
(7) leukotriene LTC4 -, LTD4/LTE4 - and LTB4 -inhibitors;
(8) PAF-receptor antagonists;
(9) gold in the form of an aurothio group together with one or more
hydrophilic groups;
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(10) immunosuppressive agents selected from the group consisting of
cyclosporine, azathioprine and methotrexate;
(1 I) anti-inflammatory glucocorticoids;
(12) penicillamine;
(13) hydroxychloroquine;
(14) anti-gout agents including colchicine; xanthine oxidase inhibitors
including allopurinol; and uricosuric agents selected from probenecid,
sulfinpyrazone and benzbromarone;
C. where older mammals are being treated for disease conditions,
'10 syndromes and symptoms found in geriatric mammals, said inhibitory
combination is administered in combination with one or more members
independently selected from the group consisting essentially of:
(1) cognitive therapeutics to counteract memory loss and impairment;
(2) anti-hypertensives and other cardiovascular drugs intended to offset the
consequences of atherosclerosis, hypertension, myocardial ischemia, angina,
congestive heart failure and myocardial infarction, selected from the group
consisting of:
a. diuretics;
b. vasodilators;
c. (3-adrenergic receptor antagonists;
d. angiotensin-II converting enzyme inhibitors (ACE-inhibitors), alone or
optionally together with neutral endopeptidase inhibitors;
e. angiotensin II receptor antagonists;
f. renin inhibitors;
g. calcium channel blockers;
h. sympatholytic agents;
i. a2-adrenergic agonists;
j. a-adrenergic receptor antagonists; and
k. HMG-CoA-reductase inhibitors (anti-hypercholesterolemics);
(3) antineoplastic agents selected from:
a. antimitotic drugs selected from:
i. vinca alkaloids selected from:
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[ 1 ) vinblastine and
[2] vincristine;
(4) growth hormone secretagogues;
(5) strong analgesics;
' (6) local and systemic anesthetics; and
(7) HZ -receptor antagonists, proton pump inhibitors and other
gastroprotectme agents.
The active ingredient of the present invention may be administered in
combination with inhibitors of other mediators of inflammation, comprising one
l0 or more members selected from the group consisting essentially of the
classes of
such inhibitors and examples thereof which include, matrix metalloproteinase
inhibitors, aggrecanase inhibitors, TACE inhibitors, leucotriene receptor
antagonists, IL-1 processing and release inhibitors, ILra, H, -receptor
antagonists;
kinin-B~ - and B2-receptor antagonists; prostaglandin inhibitors such as PGD-,
PGF- PGIZ - and PGE-receptor antagonists; thromboxane A2 (TXA2-) inhibitors;
5- and 12-lipoxygenase inhibitors; leukotriene LTC4 -, LTD4/L,TE4 - and LTB4 -
inhibitors; PAF-receptor antagonists; gold in the form of an aurothio group
together with various hydrophilic groups; immunosuppressive agents, e.g.,
cyclosporine, azathioprine and methotrexate; anti-inflammatory
glucocorticoids;
penicillamine; hydroxychloroquine; anti-gout agents, e.g., colchicine,
xanthine
oxidase inhibitors, e.g., allopurinol and uricosuric agents, e.g., probenecid,
sulfinpyrazone and benzbromarone.
The combinations of the present invention may also be used in
combination with anticancer agents such as endostatin and angiostatin or
cytotoxic
drugs such as Adriamycin, daunomycin, cis-platinum, etoposide, taxol, taxotere
and alkaloids, such as vincristine and anti metabolites such as methotrexate.
The combinations of the present invention may also be used in
combination with anti-hypertensives and other cardiovascular drugs intended to
offset the consequences of atherosclerosis, including hypertension, myocardial
ischemia including angina, congestive heart failure and myocardial infarction,
selected from vasodilators such as hydralazine, (3-adrenergic receptor
antagonists
such as propranolol, calcium channel Mockers such as nifedipine, a2-adrenergic
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agonists such as clonidine, a-adrenergic receptor antagonists such as prazosin
and
HMG-CoA-reductase inhibitors (anti-hypercholesterolemics) such as lovastatin
or
atorvastatin.
The combination of the present invention may also be administered in
combination with one or more antibiotic, antifungal, antiprotozoal, antiviral
or
similar therapeutic agents.
The combinations of the present invention may also be used in
combination with CNS agents such as antidepressants (such as sertraline), anti-
Parkinsonian drugs (such as L-dopa, requip, mirapex, MAOB inhibitors such as
selegine and rasagiline, come inhibitors such as Tasmar, A-2 inhibitors,
dopamine
reuptake inhibitors, NMDA antagonists, nicotine agonists, dopamine agonists
and
inhibitors of neuronal nitric oxide synthase) and anti-Alzheimer's drugs such
as
donepezil, tacrine, COX-2 inhibitors, propentofylline or metryfonate.
The combinations of the present invention may also be used in
l5 combination with osteoporosis agents such as roloxifene, lasofoxifene,
droloxifene or fosomax and immunosuppressant agents such as FK-506 and
rapamycin.
The present invention also relates to the formulation of the combination of
the present invention alone or with one or more other therapeutic agents which
are
to form the intended combination, including wherein said different drugs have
varying half-lives, by creating controlled-release forms of said drugs with
different release times which achieves relatively uniform dosing; or, in the
case of
non-human patients, a medicated feed dosage form in which said drugs used in
the
combination are present together in admixture in the feed composition. There
is
further provided in accordance with the present invention co-administration in
which the combination of drugs is achieved by the simultaneous administration
of
said drugs to be given in combination; including co-administration by means of
different dosage forms and routes of administration; the use of combinations
in
accordance with different but regular and continuous dosing schedules whereby
desired plasma levels of said drugs involved are maintained in the patient
being
treated, even though the individual drugs making up said combination are not
being administered to said patient simultaneously.
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The term "drugs", which is synonymous with the phrases "active
components", "active compounds", and "active ingredients", includes celecoxib,
or a pharmaceutically acceptable salt thereof, valdecoxib, or a
pharmaceutically
acceptable salt thereof, and an allosteric carboxylic inhibitor of MMP-13, or
a
liharmaceutically acceptable salt thereof, and may-further include one or two
of
the,other therapeutic agents described above.
The invention method is useful in human and veterinary medicines for
treating mammals suffering from one or more of the above-listed diseases and
disorders.
The term "mammal" includes humans, companion animals such as cats
and dogs, primates such as monkeys and chimpanzees, and livestock animals such
as horses, cows, pigs, and sheep.
The phrase "livestock animals" as used. herein refers to domesticated
quadrupeds, which includes those being raised for meat and various byproducts,
e.g., a bovine animal including cattle and other members of the genus Bos, a
porcine animal including domestic swine and other members of the genus Sus, an
ovine animal including sheep and other members of the genus Ovis, domestic
goats and other members of the genus Capra; domesticated quadrupeds being
raised for specialized tasks such as use as a beast of burden, e.g., an equine
animal
including domestic horses and other members of the family Equidae, genus
Equus, or for searching and sentinel duty, e.g., a canine animal including
domestic
dogs and other members of the genus Canis; and domesticated quadrupeds being
raised primarily for recreational purposes, e.g., members of Equus and Canis,
as
well as a feline animal including domestic cats and other members of the
family
Felidae, genus Felis.
All that is required to practice the method of this invention is to administer
a combination of celecoxib, or a pharmaceutically acceptable salt thereof, or
valdecoxib, or a pharmaceutically acceptable salt thereof, and an allosteric
carboxylic inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof,
in
an amount that is therapeutically effective for preventing, inhibiting, or
reversing
the condition being treated. The invention combination can be administered
directly or in a pharmaceutical composition as described below.
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A therapeutically effective amount, or, simply, effective amount, of an
invention combination will generally be from about 1 to about 300 mg/kg of
subject body weight of valdecoxib, or a pharmaceutically acceptable salt
thereof,
or celecoxib, or a pharmaceutically acceptable salt thereof, and from about 1
to
about 300 mg/kg of subject body weight of an allosteric carboxylic inhibitor
of
MMP-13, or a pharmaceutically acceptable salt thereof. Typical doses will be
from about 10 to about 5000 mg/day for an adult subject of normal weight for
each component of the combination. In a clinical setting, regulatory agencies
such
as, for example, the Food and Drug Administration ("FDA") in the U.S. may
require a particular therapeutically effective amount.
In determining what constitutes an effective amount or a therapeutically
effective amount of an invention combination for treating, preventing, or
reversing
one or more symptoms of any one of the diseases and disorders described above
that are being treated according to the invention methods, a number of factors
will
generally be considered by the medical practitioner or veterinarian in view of
the
experience of the medical practitioner or veterinarian, including the Food and
Drug Administration guidelines, or guidelines from an equivalent agency,
published clinical studies, the subject's (e.g., mammal's) age, sex, weight
and
general condition, as well as the type and extent of the disease, disorder or
condition being treated, and the use of other medications, if any, by the
subject.
As such, the administered dose may fall within the ranges or concentrations
recited above, or may vary outside them, ie, either below or above those
ranges,
depending upon the requirements of the individual subject, the severity of the
condition being treated, and the particular therapeutic formulation being
employed. Determination of a proper dose for a particular situation is within
the
skill of the medical or veterinary arts. Generally, treatment may be initiated
using
smaller dosages of the invention combination that are less than optimum for a
particular subject. Thereafter, the dosage can be increased by small
increments
until the optimum effect under the circumstance is reached. For convenience,
the
total daily dosage may be divided and administered in portions during the day,
if
desired.
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Pharmaceutical compositions, described briefly here and more fully below,
of an invention combination may be produced by formulating the invention
combination in dosage unit form with a pharmaceutical carrier. Some examples
of
dosage unit forms are tablets, capsules, pills, powders, aqueous and
nonaqueous
oral solutions and suspensions, and parenteral solutions packaged in
containers
containing either one or some larger number of dosage units and capable of
being
subdivided into individual doses. Alternatively, the active components of the
invention combination may be formulated separately.
Some examples of suitable pharmaceutical carriers, including
pharmaceutical diluents, are gelatin capsules; sugars such as lactose and
sucrose;
starches such as corn starch and potato starch; cellulose derivatives such as
sodium carboxymethyl cellulose, ethyl cellulose, methyl cellulose, and
cellulose
acetate phthalate; gelatin; talc; stearic acid; magnesium stearate; vegetable
oils
such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil, and oil
of
theobroma; propylene glycol, glycerin; sorbitol; polyethylene glycol; water;
agar;
alginic acid; isotonic saline, and phosphate buffer solutions; as well as
other
compatible substances normally used in pharmaceutical formulations.
The compositions to be employed in the invention can also contain other
components such as coloring agents, flavoring agents, andlor preservatives.
These
materials, if present, are usually used in relatively small amounts. The
compositions can, if desired, also contain other therapeutic agents commonly
employed to treat any of the above-listed diseases and disorders.
The percentage of the active ingredients of celecoxib, or a
pharmaceutically acceptable salt thereof, or valdecoxib, or a pharmaceutically
acceptable salt thereof, and an allosteric carboxylic inhibitor of MMP-13, or
a
pharmaceutically acceptable salt thereof, combination in the foregoing
compositions can be varied within wide limits, but for practical purposes it
is
preferably present in a total concentration of at least 10% in a solid
composition
and at least 2% in a primary liquid composition. The most satisfactory
compositions are those in which a much higher proportion of the active
ingredients are present, for example, up to about 95%.
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Preferred routes of administration of an invention combination are oral or
parenteral. However, another route of administration may be preferred
depending
upon the condition being treated. For exampled, topical administration or
administration by injection may be preferred for treating conditions localized
to
the skin or a joint. Administration by transdermal patch may be preferred
where,
for example, it is desirable to effect sustained dosing.
It should be appreciated that the different routes of administration may
require different dosages. For example, a useful intravenous ("IV") dose is
between 5 and 50 mg, and a useful oral dosage is between 20 and 800 mg, both
l0 for each of celecoxib, or a pharmaceutically acceptable salt thereof, or
valdecoxib,
or a pharmaceutically acceptable salt thereof, and an allosteric carboxylic
inhibitor
of MMP-13, or a pharmaceutically acceptable salt thereof. The dosage is within
the dosing range used in treatment of the above-listed diseases, or as would
be
determined by the needs of the patient as described by the physician.
The invention combination may be administered in any form. Preferably,
administration is in unit dosage form. A unit dosage form of the invention
combination to be used in this invention may also comprise other compounds
useful in the therapy of diseases described above. A further description of
pharmaceutical formulations useful for administering the invention
combinations
is provided below.
The active components of the invention combination, including celecoxib,
or a pharmaceutically acceptable salt thereof, or valdecoxib, or a
pharmaceutically
acceptable salt thereof, and an allosteric carboxylic inhibitor of MMP-13, or
a
pharmaceutically acceptable salt thereof, and other compounds as described
above, if any, may be formulated together or separately and may be
administered
together or separately. The particular formulation and administration regimens
used may be tailored to the particular patient and condition being treated by
a
practitioner of ordinary skill in the medical or pharmaceutical arts.
The advantages of using an invention combination comprising celecoxib,
or a pharmaceutically acceptable salt thereof, or valdecoxib, or a
pharmaceutically
acceptable salt thereof, and an allosteric carboxylic inhibitor of MMP-13, or
a
pharmaceutically acceptable salt thereof, in a method of the instant invention
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include the nontoxic nature of the compounds which comprise the combination at
and substantially above therapeutically effective doses, their ease of
preparation,
the fact that the compounds are well-tolerated, and the ease of topical, N, or
oral
administration of the drugs.
' Another important advantage is that the present invention combinations
more effectively target a particular disease that is responsive to inhibition
of
MMP-I 3 with fewer undesirable side effects than similar combinations that
contain MMP-13 inhibitors that are not allosteric carboxylic inhibitors of MMP-
13. This is so because the instant allosteric carboxylic inhibitors of MMP-13,
or a
pharmaceutically acceptable salt thereof, do not directly, or indirectly via a
bridging water molecule, ligate, coordinate to, or bind to the catalytic zinc
cation
of MMP-13, but instead bind at a different location from where natural
substrate
binds to MMP-13. The binding requirements of an allosteric MMP-13 binding site
are unique to MMP-I 3, and account for the specificity of the instant
allosteric
carboxylic inhibitors of MMP-13 for inhibiting MMP-13 over any other MMP
enzyme. This binding mode has not been reported in the art. Indeed, prior art
inhibitors of MMP-13 bind to the catalytic zinc canons of other MMP enzymes as
well as to the catalytic zinc cation of MMP-13 and, and are consequently
significantly less selective inhibitors of MMP-13 enzyme.
The instant allosteric carboxylic inhibitors of MMP-13 are thus
therapeutically superior to other inhibitors of MMP-13, or even tumor necrosis
factor-alpha converting enzyme ("TACE"), because of fewer undesirable side
effects from inhibition of the other MMP enzymes or TACE. For example,
virtually all prior art MMP inhibitors tested clinically to date have
exhibited an
undesirable side effect known as muscoloskeletal syndrome ("MSS"). MSS is
associated with administering an inhibitor of multiple MMP enzymes or an
inhibitor of a particular MMP enzyme such as MMP-1. MSS will be significantly
reduced in type and severity by administering the invention combination
instead
of any combination of a prior art MMP-l3 inhibitor with celecoxib or
valdecoxib,
or a pharmaceutically acceptable salt thereof. The invention combinations are
superior to similar combinations that include a COX-2 selective inhibitor with
an
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MMP inhibitor that interacts with the catalytic zinc canon of the MMP-13
enzyme
as discussed above, even if that inhibitor shows some selectivity for the MMP-
13.
This advantage of the instant combinations will also significantly increase
the likelihood that agencies which regulate new drug approvals, such as the
United States Food and Drug Administration, will approve the instant
combination versus a competing similar combination as discussed above even in
the unlikely event that the two combinations behaved similarly in clinical
trials.
These regulatory agencies are increasingly aware that clinical trials, which
test
drug in limited population groups, do not always uncover safety problems with
a
drug, and thus all other things being equal, the agencies will favor the drug
with
the lowest odds of producing undesirable side effects.
Another important advantage is that the independent anti-inflammatory
and pain reducing properties described above for valdecoxib and celecoxib and
the disease modifying properties of allosteric carboxylic inhibitors of MMP-13
provide patients suffering from cartilage damage, arthritis, inflammation
and/or
pain with both relief of symptoms and prevention or inhibition of the
underlying
disease pathology such as cartilage degradation.
A further advantage of the invention combination is administration of the
combination to treat a disease or disorder in a mammal may allow lower doses
of
valdecoxib, or a pharmaceutically acceptable salt thereof, or celecoxib, or a
pharmaceutically acceptable salt thereof, and/or an allosteric carboxylic
inhibitor
of MMP-l3 of the combination to be used than would be used if valdecoxib, or a
pharmaceutically acceptable salt thereof, or celecoxib, or a pharmaceutically
acceptable salt thereof, and the allosteric carboxylic inhibitor of MMP-13
were
each administered alone. This advantage is a result of an unexpected
synergistic
therapeutically beneficial effect on inhibition of cartilage damage or
alleviation of
pain for the combination over the sum of the therapeutic effects for each
component of the combination administered alone.
Some of the compounds utilized in an invention combination are capable
of further forming pharmaceutically acceptable salts, including, but not
limited to,
acid addition and/or base salts. The acid addition salts are formed from basic
compounds, whereas the base addition salts are formed from acidic compounds.
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All of these forms are within the scope of the compounds useful in the
invention
combination.
Pharmaceutically acceptable acid addition salts of the basic compounds
useful in the invention combination include nontoxic salts derived from
inorganic
kids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic,
hydroiodic,
hydrofluoric, phosphorous, and the like, as well nontoxic salts derived from
organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-
substituted
alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids,
aliphatic and aromatic sulfonic acids, etc. Such salts thus include sulfate,
pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate,
monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate,
chloride, bromide, iodide, acetate, trifluoroacetate, propionate, caprylate,
isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate,
maleate,
mandelate, benzoate, chlorobenzoate; methylbenzoate, dinitrobenzoate,
phthalate,
benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, malate,
tartrate,
methanesulfonate, and the like. Also contemplated are salts of amino acids
such as
arginate and the like and gluconate, galacturonate (see, for example, Berge
S.M.
et al., "Pharmaceutical Salts," J. of Pharma. Sci., 1977;66:1 ).
An acid addition salt of a basic compound useful in the invention
combination is prepared by contacting the free base form of the compound with
a
sufficient amount of a desired acid to produce a nontoxic salt in the
conventional
manner. The free base form of the compound may be regenerated by contacting
the acid addition salt so formed with a base, and isolating the free base form
of the
compound in the conventional manner. The free base forms of compounds
prepared according to a process of the present invention differ from their
respective acid addition salt forms somewhat in certain physical properties
such as
solubility, crystal structure, hygroscopicity, and the like, but otherwise
free base
forms of the compounds and their respective acid addition salt forms are
equivalent for purposes of the present invention.
A pharmaceutically acceptable base addition salt of an acidic compound
useful in the invention combination may be prepared by contacting the free
acid
form of the compound with a nontoxic metal cation such as an alkali or
alkaline
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earth metal canon, or an amine, especially an organic amine. Examples of
suitable
metal cations include sodium cation (Na+), potassium canon (K+), magnesium
canon (Mg2+), calcium cation (Ca2+), and the like. Examples of suitable amines
are N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine,
dicyclohexylamine, ethylenediamine, N-methylglucamine, and procaine (see, for
example, Berge, supra., 1977).
A base addition salt of an acidic compound useful in the invention
combination may be prepared by contacting the free acid form of the compound
with a sufficient amount of a desired base to produce the salt in the
conventional
manner. The free acid form of the compound may be regenerated by contacting
the salt form so formed with an acid, and isolating the free acid of the
compound
in the conventional manner. The free acid forms of the compounds useful in the
invention combination differ from their respective salt forms somewhat in
certain
physical properties such as solubility, crystal structure, hygroscopicity, and
the
like, but otherwise the salts are equivalent to their respective free acid for
purposes of the present invention.
Certain of the compounds useful in the invention combination can exist in
unsolvated forms as well as solvated forms, including hydrated forms. In
general,
the solvated forms, including hydrated forms, are equivalent to unsolvated
forms
and are encompassed within the scope of the present invention.
Certain of the compounds useful in the invention combination possess one
or more chiral centers, and each center may exist in the R or S configuration.
An
invention combination may utilize any diastereomeric, enantiomeric, or
epimeric
form of a compound useful in the invention combination, as well as mixtures
thereof.
Additionally, certain compounds useful in the invention combination may
exist as geometric isomers such as the entgegen (E) and zusammen (Z) isomers
of
1,2-disubstituted alkenyl groups or cis and traps isomers of disubstituted
cyclic
groups. An invention combination may utilize any cis, traps, syn, anti,
entgegen (E), or zusammen (Z) isomer of a compound useful in the invention
combination, as well as mixtures thereof.
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Certain compounds useful in the invention combination can exist as two or
more tautomeric forms. Tautomeric forms of the compounds may interchange, for
example, via enolization/de-enolization, l,2-hydride, 1,3-hydride, or 1,4-
hydride
shifts, and the like. An invention combination may utilize any tautomeric form
of
a compound useful in the invention combination, as well as mixtures thereof.
The syntheses of valdecoxib, or a pharmaceutically acceptable salt thereof,
and celecoxib, or a pharmaceutically acceptable salt thereof, are well-known
in
the art, and have even been carried out to produce commercial-scale quantities
of
compound. The synthesis of allosteric inhibitors of MMP-13 are taught in the
patent applications incorporated above by reference.
Intermediates for the synthesis of valdecoxib, or a pharmaceutically
acceptable salt thereof, celecoxib, or a pharmaceutically acceptable salt
thereof,
and an allosteric carboxylic inhibitor of MMP-13, or a pharmaceutically
acceptable salt thereof, useful in the invention combination may be prepared
by
one of ordinary skill in the art of organic chemistry by adapting various
synthetic
procedures incorporated by reference above or that are well-known in the art
of
organic chemistry. These synthetic procedures may be found in the literature
in,
for example, Reagents for Organic Synthesis, by Fieser and Fieser, John Wiley
&
Sons, Inc, New York, 2000; Comprehensive Organic Transformations, by Richard
C. Larock, VCH Publishers, Inc, New York, 1989; the series Compendium of
Organic Synthetic Methods,1989,by Wiley-Interscience; the text Advanced
Organic Chemistry, 4th edition, by Jerry March, Wiley-Interscience, New
York,1992; or the Handbook of Heterocyclic Chemistry by Alan R. Katritzky,
Pergamon Press Ltd, London, 1985, to name a few. Alternatively, a skilled
artisan
may find methods useful for preparing the intermediates in the chemical
literature
by searching widely available databases such as, for example, those available
from the Chemical Abstracts Service, Columbus, Ohio, or MDL Information
Systems GmbH (formerly Beilstein Information Systems GmbH), Frankfurt,
Germany.
Preparations of the compounds useful in an invention combination may
use starting materials, reagents, solvents, and catalysts that may be
purchased
from commercial sources or they may be readily prepared by adapting procedures
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in the references or resources cited above. Commercial sources of starting
materials, reagents, solvents, and catalysts useful in preparing invention
compounds include, for example, The Aldrich Chemical Company, and other
subsidiaries of Sigma-Aldrich Corporation, St. Louis, Missouri, BACHEM,
BACHEM A.G., Switzerland, or Lancaster Synthesis Ltd, United Kingdom.
Syntheses of some compounds useful in the invention combination may
utilize starting materials, intermediates, or reaction products that contain a
reactive
functional group. During chemical reactions, a reactive functional group may
be
protected from reacting by a protecting group that renders the reactive
functional
group substantially inert to the reaction conditions employed. A protecting
group
is introduced onto a starting material prior to carrying out the reaction step
for
which a protecting group is needed. Once the protecting group is no longer
needed, the protecting group can be removed. It is well within the ordinary
skill in
the art to introduce protecting groups during a synthesis of valdecoxib, or a
pharmaceutically acceptable salt thereof, or celecoxib, or a pharmaceutically
acceptable salt thereof, or an allosteric carboxylic inhibitor of MMP-13, or a
pharmaceutically acceptable salt thereof, and then later remove them.
Procedures
for introducing and removing protecting groups are known and referenced such
as,
for example, in Protective Groups in Organic Synthesis, 2nd ed., Greene T.W.
and
Wuts P.G., John Wiley & Sons, New York: New York, 1991, which is hereby
incorporated by reference.
Thus, for example, protecting groups such as the following may be utilized
to protect amino, hydroxyl, and other groups: carboxylic acyl groups such as,
for
example, formyl, acetyl, and trifluoroacetyl; alkoxycarbonyl groups such as,
for
example, ethoxycarbonyl, tert-butoxycarbonyl (BOC), ~,(3,(~-
trichloroethoxycarbonyl (TCEC), and (3-iodoethoxycarbonyl; aralkyloxycarbonyl
groups such as, for example, benzyloxycarbonyl (CBZ), para-
methoxybenzyloxycarbonyl, and 9-fluorenylmethyloxycarbonyl (FMOC);
trialkylsilyl groups such as, for example, trimethylsilyl (TMS) and tert-
butyldimethylsilyl (TBDMS); and other groups such as, for example,
triphenylmethyl (trityl), tetrahydropyranyl, vinyloxycarbonyl, ortho-
nitrophenylsulfenyl, diphenylphosphinyl, para-toluenesulfonyl (Ts), mesyl,
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trifluoromethanesulfonyl, and benzyl. Examples of procedures for removal of
protecting groups include hydrogenolysis of CBZ groups using, for example,
hydrogen gas at 50 psi in the presence of a hydrogenation catalyst such as 10%
palladium on carbon, acidolysis of BOC groups using, for example, hydrogen
chloride in dichloromethane, trifluoroacetic acid (TFA) in dichloromethane,
and
the,like, reaction of silyl groups with fluoride ions, and reductive cleavage
of
TCEC groups with zinc metal.
Preparations of valdecoxib, or a pharmaceutically acceptable salt thereof,
or an allosteric carboxylic inhibitor of MMP-13, or a pharmaceutically
acceptable
salt thereof, useful in the invention combination are incorporated by
reference to
the patents, patent applications, and patent application publications
described
above.
Allosteric carboxylic inhibitors of MMP-13 useful in the present invention
combinations may be prepared by one of ordinary skill in the art of synthetic
organic chemistry readily adapting known literature methods. Additional
methods
of preparation are described in co-pending PCT international applications and
their corresponding United States nonprovisional application numbers
10/071,032;
10/075,918; 10/075,073; 10/075,069; 10/075,954; 10/075,654; 10/074,646;
10/075,909; and 10/071,073, and the related United States provisional
application
numbers 60/268,780; 60/268,736; 60/268,756; 60/268,821; 60/268,861;
60/268,757; 60/268,782; 60/268,779; and 60/268,781, respectively, all
provisional
applications filed on February 14, 2001, and from which benefit of priority is
claimed. All of the PCT International applications, United States provisional
applications, and United States nonprovisional applications have been
incorporated herein by reference above.
EXAMPLES OF ALLOSTERIC CARBOXYLIC INHIBITORS OF MMP-13
1. Examples of thiazolopyrimidinedione allosteric inhibitors of MMP-13:
The syntheses of thiazolopyrimidinediones useful as allosteric inhibitors of
MMP-13 are described in our co-pending U.S. nonprovisional application number
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10/071,032, the corresponding PCT International application number
PCT/IB02/00313, and the priority application U.S. provisional application
number
60/268,780, filed on February 14, 2001.
One example is named and drawn below:
6-Benzyl-5,7-dioxo-6,7-dihydro-SH-thiazolo[3,2-cJpyrimidine-2-carboxylic acid
benzyl ester
0
o~~
N N I O
O
It should be appreciated that the compound drawn above has first and
second hydrophobic groups and first, second and third hydrogen bond acceptors.
The first hydrophobic group locates in the S 1' pocket of the enzyme and its
hydrophobic aryl ring interacts with the aryl rings of His222 and Tyr244. The
second hydrophobic group is open to solvent and forms hydrophobic interactions
with the aryl rings of e.g. Phe252 and Tyr246. The three hydrogen bond
acceptors
interact respectively with Thr245, Thr247 and Met 253.
2. Examples of isophthalic acid allosteric inhibitors of MMP-13:
The syntheses of isophthalic acid derivatives are described in our co
pending United States nonprovisional application number 10/075,918, the
corresponding PCT International application number PCT/IB02/00344, and the
priority application United States provisional application number 60/268,736,
filed on February 14, 2001.
Binding to MMP-13 of a representative example of one of the isophthalic
acid derivatives is as described above for Example 1. It will be observed that
the
compounds of this series have two hydrophobic groups and two hydrogen bond
acceptors.
3. Examples of fused bicyclic pyrimidone allosteric inhibitors of MMP-13:
The syntheses of fused bicyclic pyrimidone allosteric inhibitors of MMP-
l3 are described in co-pending United States nonprovisional application number
7 0/075,073, the corresponding PCT International application number
PCT/IB02/00204, and the priority application United States provisional
application number 60/268,756, filed on February 14, 2001.
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Binding to MMP-13 of a representative compound of the fused bicyclic
pyrimidone allosteric inhibitors of MMP-13 is through two hydrophobic groups
and three hydrogen bond acceptors, the third hydrogen bond acceptor binding to
Met 253 and also via a bridging water molecule to the backbone carbonyl of
His251.
4. Examples of substituted quinazoline allosteric inhibitors of MMP-13:
The syntheses of quinazoline allosteric inhibitors of MMP-13 are
described in our co-pending United States nonprovisional application number
10/075,954, the related PCT International application number PCT/EP02/01979,
and the corresponding priority United States provisional application number
60/268,661, filed on February 14, 2001.
Binding to MMP-13 of the compound of Example 35 is based on two
hydrophobic groups and three hydrogen bond acceptors. As in the
thiazolopyrimidinediones, the third hydrogen bond acceptor binds both to Met
253 and via a bridging water molecule to the backbone carbonyl oxygen of His
251. It will also be noted from the above table that some compounds in this
series
do not have a second hydrophobic group, but nevertheless bind to MMP-13 and
exhibit a useful inhibitory activity.
5. Examples of pyrido[2,3-d]pyrimidines:
The syntheses of pyrido[2,3-d]pyrimidine allosteric inhibitors of MMP-13
are also described in our co-pending United States nonprovisional application
number 10/075,954, the related PCT International application number
PCT/BP02/01979, and the corresponding priority United States provisional
application number 60/268,661, filed on February 14, 2001.
6. Examples of fused triazolo-quinazoline allosteric inhibitors of MMP-13:
Syntheses of fused triazolo-quinazoline allosteric inhibitors of MMP-13
are described in our co-pending United States nonprovisional application
number
10/075,654, the related PCT International application number PCT/FR02/00504,
and the priority application United States provisional application number
60/268,757, filed on February 14, 2001.
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Binding of a representative compound in the fused triazolo-quinazoline,
Example 57 involves first and second hydrophobic groups and first, second and
third hydrogen bond acceptors.
7. Examples of l,l-dioxy-benzo-(1,2,4)-thiadiazine allosteric inhibitors of
MMP-
13:
The syntheses of 1,1-dioxy-benzo-(1,2,4)-thiadiazine allosteric inhibitors
of MMP-13 are described in our co-pending United States nonprovisional
application number 10/074,646, the related PCT International application
number
PCT/IB02/00083, and the priority application United States provisional
l0 application number 60/268,782, filed on February 14, 2001.
For illustration purposes, examples of allosteric carboxylic inhibitors of
MMP-13 are described below. The allosteric carboxylic inhibitors of MMP-l3
have been evaluated in standard assays for their ability to inhibit the
catalytic
activity of various MMP enzymes. The assays used to evaluate the MMP
biological activity of the invention compounds are well-known and routinely
used
by those skilled in the study of MMP inhibitors and their use to treat
clinical
conditions. For example, allosteric carboxylic inhibitors of MMP-13 may be
readily identified by assaying a test compound for inhibition of MMP-13
according to Biological Methods 1 or 2, and further assaying the test compound
for allosteric inhibition of MMP-13 according to Biological Methods 3 or 4, as
described below.
Examples of allosteric carboxylic inhibitors of MMP-13 are provided
below. The compounds have been shown to be potent and selective inhibitors of
MMP-13 catalytic domain versus full-length MMP-1 and MMP-3 catalytic
domain. Potencies with MMP-13 catalytic domain for the allosteric inhibitors
of
MMP-13 typically range from about 0.001 pM to about 1 pM. Some compounds
were further screened with full-length MMP-2, full-length MMP-7, full-length
MMP-9, and MMP-14 catalytic domain, and were found to be selective inhibitors
of MMP-13 versus these other MMP enzymes also. Selectivity of the allosteric
inhibitors of MMP-13 for MMP-13 catalytic domain versus another MMP enzyme
(full-length or catalytic domain), as determined by dividing the ICSO for the
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inhibitor with a comparator MMP enzyme by the ICSO of the inhibitor with MMP-
13 catalytic domain, typically ranged from 5 to 50,000 fold.
The allosteric carboxylic inhibitors of MMP-13 were assayed for
inhibition of MMP-13 and for allosteric inhibition of MMP-13 and certain other
MMP enzymes according to Biological Methods 1 to 4, which are described
immediately below. The assays measure the amount by which a test compound
reduces the hydrolysis of a thiopeptolide substrate catalyzed by a matrix
metalloproteinase enzyme. Such assays are described in detail by Ye et al., in
Biochemistry, 1992;31 (45):11231-11235, which is incorporated herein by
reference. One such assay is described below in Biological Method 1.
Some of the particular methods described below use the catalytic domain
of the MMP-13 enzyme, namely matrix metalloproteinase-13 catalytic domain
("MMP-13CD"), rather than the corresponding full-length enzyme, MMP-13. It
has been shown previously by Ye Qi-Zhuang, Hupe D., and Johnson L. (Current
Medicinal Chemistry, 1996;3:407-418) that inhibitor activity against a
catalytic
domain of an MMP is predictive of the inhibitor activity against the
respective
full-length MMP enzyme.
BIOLOGICAL METHOD 1
Thiopeptolide substrates show virtually no decomposition or hydrolysis at
or below neutral pH in the absence of a matrix metalloproteinase enzyme. A
typical thiopeptolide substrate commonly utilized for assays is Ac-Pro-Leu-Gly-
thioester-Leu-Leu-Gly-OEt. A 100 ~L assay mixture will contain SO mM of N-2-
hydroxyethylpiperazine-N'-2-ethanesulfonic acid buffer ("HEPES," pH 7.0),
10 mM CaCl2, 100 ~M thiopeptolide substrate, and l mM 5,5'-dithio-bis-(2-nitro-
benzoic acid) (DTNB). The thiopeptolide substrate concentration may be varied,
for example from 10 to 800 ~M to obtain Km and Kcat values. The change in
absorbance at 405 nm is monitored on a Thermo Max microplate reader
(molecular Devices, Menlo Park, CA) at room temperature (22°C). The
calculation of the amount of hydrolysis of the thiopeptolide substrate is
based on
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E412 = 13600 M-1 cm-1 for the DTNB-derived product 3-carboxy-
4-nitrothiophenoxide. Assays are carried out with and without matrix
metalloproteinase inhibitor compounds, and the amount of hydrolysis is
compared
for a determination of inhibitory activity of the test compounds.
Test compounds were evaluated at various concentrations in order to
determine their respective ICSp values, the micromolar concentration of
compound required to cause a 50% inhibition of catalytic activity of the
respective
enzyme.
It should be appreciated that the assay buffer used with MMP-3CD was
50 mM N-morpholinoethane sulfonate ("MES") at pH 6.0 rather than the HEPES
buffer at pH 7.0 described above.
BIOLOGICAL METHOD 2
The test described above for the inhibition of MMP-l 3 was also adapted
and used to determine the ability of the allosteric carboxylic inhibitors of
MMP-13
to inhibit the matrix metalloproteases MMP-1, MMP-2, MMP-3, MMP-7,
MMP-9, MMP-12 and MMP-14. Allosteric carboxylic inhibitors of MMP-13 have
been evaluated for their ability to inhibit MMP-13 and other MMPs using, for
example, MMP-1 FL, which refers to full length interstitial collagenase;
MMP-2FL, which refers to full length Gelatinase A; MMP-3CD, which refers to
the catalytic domain of stromelysin; MMP-7FL, which refers to full length
matrilysin; MMP-9FL, which refers to full length Gelatinase B; MMP-13CD,
which refers to the catalytic domain of collagenase 3; and MMP-14CD, which
refers to the catalytic domain of MMP-14. Test compounds can be evaluated at
various concentrations in order to determine their respective IC50 values, the
micromolar concentration of compound required to cause a 50% inhibition of the
hydrolytic activity of the respective enzyme. The results obtained show that
the
allosteric carboxylic inhibitors of MMP-13 generally have ICSO values for
MMP-13 which are about 100 times lower than the ICSO values for the same
compounds with respect to the other matrix metalloproteases tested.
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The results of the above assays with other MMPs establish that the
allosteric carboxylic inhibitors of MMP-13 are potent and selective inhibitors
of
MMP enzymes. Because of this potent and selective inhibitory activity, the
compounds are especially useful, in combination with a selective inhibitor of
COX-2, to treat diseases mediated by the MMP enzymes and COX-2, and
particularly those mediated by MMP-13 and COX-2.
Allosteric carboxylic inhibitors of MMP-13 also may be readily identified
by assaying a test compound for inhibition of MMP-13 according to the methods
described below in Biological Methods 3 and 4.
BIOLOGICAL METHOD 3
Fluorigenic peptide-1 substrate based assay for identifying allosteric
carboxylic inhibitors of MMP-13CD:
Final assay conditions:
50 ~mM HEPES buffer (pH 7.0)
10 mM CaCl2
10 ~M fluorigenic peptide-1 ("FP1") substrate
0 or 15 mM acetohydroxamic acid (AcNHOH) = 1 Kd
2% DMSO (with or without inhibitor test compound)
0.5 nM MMP-13CD enzyme
Stock solutions:
1 ) l OX assay buffer: 500 mM HEPES buffer (pH 7.0) plus 100 mM CaCl2
2) 10 mM FPl substrate: (Mca)-Pro-Leu-Gly-Leu-(Dnp)-Dpa-Ala-Arg-NH2
(Bachem, M-1895; "A novel coumarin-labeled peptide for sensitive
continuous assays of the matrix metalloproteinases," Knight C.G.,
Willenbrock F., and Murphy, G., FEBS Lett., 1992;296:263-266). Prepared
10 mM stock by dissolving 5 mg FP1 in 0.457 mL DMSO.
3) 3 M AcNHOH: Prepared by adding 4 mL H20 and l mL l OX assay buffer to
2.25 g AcNHOH (Aldrich 15,903-4). Adjusted pH to 7.0 with NaOH. Diluted
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volume to 10 mL with H20. Final solution contained 3 M AcNHOH, 50 mM
HEPES buffer (pH 7.0), and 10 mM CaCl2.
4) AcNHOH dilution buffer: 50 mM HEPES buffer (pH 7.0) plus 10 mM CaCl2
5) MMP-13CD enzyme: Stock concentration = 250 nM.
6) Enzyme dilution buffer: 50 mM HEPES buffer (pH 7.0), 10 mM CaCl2, and
0.005% BRIJ 35 detergent (Calbiochem 203728; Protein Grade, 10%)
Procedure (for one 96-well microplate):
A. Prepared assay mixture:
1100 p.L l OX assay buffer
11 p,L 10 mM FP 1
55 p.L 3 M AcNHOH or 55 ~.L AcNHOH dilution buffer
8500 p.L H20
B. Diluted MMP-13CD to 5 nM working stock:
22 ~L MMP-13CD (250 nM)
1078 ~L enzyme dilution buffer
C. Ran kinetic assay:
1. Dispensed 2 ~.L inhibitor test sample (in 100% DMSO) into well.
2. Added 88 ~L assay mixture and mixed well, avoiding bubbles.
3. Initiated reactions with 10 ~L of 5 nM MMP-13CD; mixed well, avoiding
bubbles.
4. Immediately measured the kinetics of the reactions at room temperature.
Fluorimeter: Fmax Fluorescence Microplate Reader & SOFTMAX PRO
Version l .l software (Molecular Devices Corporation; Sunnyvale, CA
94089).
Protocol menu:
excitation: 320 nm emission: 405 nm
run time: 15 min interval: 29 sec
RFU min: -10 RFU max: 200
Vmax Points: 32/32
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D. Compared % of control activity and/or ICSp with inhibitor test compound
~AcNHOH.
Hydrolysis of the fluorigenic peptide-1 substrate, [(Mca)Pro-Leu-Gly-Leu-
Dpa-Ala-Arg-NH2; Bachem, catalog number M-1895], wherein "Mca" is
(7-methoxy-coumarin-4-yl)acetyl and "Dpa" is (3-[2,4-dinitrophenyl]-L-
2,3-diaminopropionyl), was used to screen for MMP-13 catalytic domain (CD)
inhibitors. (Dpa may also be abbreviated as "Dnp".) Reactions (100 ~.L)
contained
0.05 M Hepes buffer (pH 7), 0.01 M calcium chloride, 0.005% polyoxyethylene
(23) lauryl ether ("Brij 35"), 0 or 15 mM acetohydroxamic acid, 10 N.M FP1,
and
0.1 mM to 0.5 nM inhibitor in DMSO (2% final).
After recombinant human MMP-13CD (0.5 nM final) was added to initiate
the reaction, the initial velocity of FP1 hydrolysis was determined by
monitoring
the increase in fluorescence at 405 nm (upon excitation at 320 nm)
continuously
for up to 30 minutes on a microplate reader at room temperature.
Alternatively, an
endpoint read can also be used to determine reaction velocity provided the
initial
fluorescence of the solution, as recorded before addition of enzyme, is
subtracted
from the final fluorescence of the reaction mixture. The inhibitor was assayed
at
different concentration values, such as, for example, 100 ~M, 10 ~.M, l ~M,
100 nM, 10 nM, and 1 nM. Then the inhibitor concentration was plotted on the
X-axis against the percentage of control activity observed for inhibited
experiments versus uninhibited experiments (i.e., (velocity with inhibitor)
divided
by (velocity without inhibitor) x 100) on the Y-axis to determine ICSp values.
This determination was done for experiments done in the presence, and
experiments done in the absence, of acetohydroxamic acid. Data were fit to the
equation: percent control activity = 100/[1+(([I]/IC50)slope)], where [I] is
the
inhibitor concentration, IC50 is the concentration of inhibitor where the
reaction
rate is 50% inhibited relative to the control, and slope is the slope of the
IC50
curve at the curve's inflection point, using nonlinear least-squares curve-
sitting
equation regression.
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Results may be expressed as an ICSp Ratio (+/-) ratio, which means a ratio
of the IC50 of the inhibitor with MMP-13 and a inhibitor to the catalytic zinc
of
MMP-13, divided by the IC50 of the inhibitor with MMP-l3 without the inhibitor
to the catalytic zinc of MMP-13. Allosteric carboxylic inhibitors of MMP-13
have
an ICSp Ratio (+/-) ratio of less than 1, and are synergistic with the
inhibitor to the
catalytic zinc of MMP-13 such as, for example, AcNHOH. Compounds which are
not allosteric carboxylic inhibitors of MMP-13 will be inactive in the assay
or will
have an IC50 Ratio (+/-) of greater than 1, unless otherwise indicated.
Results can
be confirmed by kinetics experiments which are well known in the biochemical
art.
BIOLOGICAL METHOD 4
Fluorigenic peptide-1 based assay for identifying allosteric carboxylic
inhibitors of matrix metalloproteinase-13 catalytic domain ("MMP-13CD"):
In a manner similar to Biological Method 3, an assay is run wherein
1,10-phenanthroline is substituted for acetohydroxamic acid to identify
allosteric
carboxylic inhibitors of MMP-13CD.
Animal models may be used to establish that the instant allosteric
carboxylic inhibitors of MMP-13, or a pharmaceutically acceptable salt
thereof, or
an N-oxide thereof, would be useful for preventing, treating, and inhibiting
cartilage damage, and thus for treating osteoarthritis, for example.
BIOLOGICAL METHOD 5
Selective inhibitors of COX-2 may be identified by screening a test
compound in the following assays.
Human In vitro assays
Human cell-based COX-1 assay:
Human peripheral blood obtained from healthy volunteers can be diluted
to 1/10 volume with 3.8% sodium citrate solution. The platelet-rich plasma
immediately obtained can be washed with 0.14 M sodium chloride containing 12
mM Tris-HCl (pH 7.4) and 1.2 mM EDTA. Platelets can then be washed with
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platelet buffer (Hanks buffer (Ca free) containing 0.2% BSA and 20 mM Hepes).
Finally, the human washed platelets (HWP) can be suspended in platelet buffer
at
the concentration of 2.85 x 10g cells/ml and stored at room temperature until
use.
The HWP suspension (70 ~l aliquots, final 2.0 x 10' cells/ml) can be placed in
a
96-well U bottom plate and 10 ~l aliquots of 12.6 mM calcium chloride added.
Platelets can be incubated with A23187 (final 10 qM, Sigma) with test compound
(0.1 - 100 ~M) dissolved in DMSO (final concentration; less than 0.01 %) at
37°C
for 15 minutes. The reaction can be stopped by addition of EDTA (final 7.7 mM)
and TxB2 in the supernatant quantitated by using a radioimmunoassay kit
(Amersham) according to the manufacturer's procedure.
Human cell-based COX-2 assay:
The human cell based COX-2 assay can be carried out as previously
described (Moore et al., Inflamm. Res., 45, 54, 1996). Confluent human
umbilical
vein endothelial cells (HUVECs, Morinaga) in a 96-well flat bottom plate can
be
washed with 80 ml of RPMI1640 containing 2% FBS and incubated with hIL-1 (3
(final concentration 300 U/ml, R & D Systems) at 37°C for 24 hours.
After
washing, the activated HUVECs can be incubated with test compound (anal
concentration; 0.1 nM-1 ~.M) dissolved in DMSO (final concentration; less than
0.01 %) at 37°C for 20 minutes and stimulated with A23187 (final
concentration
30 mM) in Hanks buffer containing 0.2% BSA, 20 mM Hepes at 37°C for 15
minutes. 6-Keto-PGF~a, stable metabolite of PGI2, in the supernatant can be
quantitated by using a radioimmunoassay method (antibody; Preseptive
Diagnostics, SPA; Amersham).
Canine In vitro assays:
The following canine cell based COX 1 and COX-2 assays have been
reported in Ricketts et al., Evaluation of Selective Inhibition of Canine
Cyclooxygenase 1 and 2 by Carprofen and Other Nonsteroidal Anti-inflammatory
Drugs, American Journal of Veterinary Research, 59 (11), 1441-1446.
Protocol for Evaluation of Canine COX-1 Activity:
Test compounds can be solubilized and diluted the day before the assay
can be to be conducted with 0.1 mL of DMSO/9.9 mL of Hank's balanced salts
solution (HBSS) and stored overnight at 4°C. On the day that the assay
can be
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carried out, citrated blood can be drawn from a donor dog, centrifuged at 190
x g
for 25 minutes at room temperature and the resulting platelet-rich plasma can
then
be transferred to a new tube for further procedures. The platelets can be
washed
by centrifuging at 1500 x g for 10 minutes at room temperature. The platelets
can
be washed with platelet buffer comprising Hank's buffer (Ca free) with 0.2%
bovine serum albumin (BSA) and 20 mM HEPES. The platelet samples can then
be adjusted to 1.5 x 10~/mL, after which 50 pl of calcium ionophore (A23187)
together with a calcium chloride solution can be added to 50 pl of test
compound
dilution in plates to produce final concentrations of 1.7 pM A23187 and 1.26
mM
l0 Ca. Then, 100 pl of canine washed platelets can be added and the samples
can be
incubated at 37°C for 15 minutes, after which the reaction can be
stopped by
adding 20 ~1 of 77 mM EDTA. The plates can then be centrifuged at 2000 x g for
minutes at 4°C, after which 50 p.l of supernatant can be assayed for
thromboxane BZ (TXB2) by enzyme-immunoassay (EIA). The pg/mL of TXBZ
can be calculated from the standard line included on each plate, from which it
can
be possible to calculate the percent inhibition of COX-1 and the ICSO values
for
the test compounds.
Protocol for Evaluation of Canine COX-2 Activity:
A canine histocytoma (macrophage-like) cell line from the American Type
Culture Collection designated as DH82, can be used in setting up the protocol
for
evaluating the COX-2 inhibition activity of various test compounds. There can
be
added to flasks of these cells 10 ~tg/mL of LPS, after which the flask
cultures can
be incubated overnight. The same test compound dilutions as described above
for
the COX-1 protocol can be used for the COX-2 assay and can be prepared the day
before the assay can be carried out. The cells can be harvested from the
culture
flasks by scraping and can then be washed with minimal Eagle's media (MEM)
combined with 1 % fetal bovine serum, centrifuged at 1500 rpm for 2 minutes
and
adjusted to a concentration of 3.2 x l05 cells/mL. To 50 ~.1 of test compound
dilution there can be added SO p.l of arachidonic acid in MEM to give a 10 ~tM
final concentration and there can be added as well 100 ~.1 of cell suspension
to
give a final concentration of 1.6 x 105 cells/mL. The test sample suspensions
can
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be incubated for 1 hour and then centrifuged at 1000 rpm for 10 minutes at
4° C,
after which 50 pl aliquots of each test compound sample can be delivered to
EIA
plates. The EIA can be performed for prostaglandin E2 (PGE2) and the pg/mL
concentration of PGEZ can be calculated from the standard line included on
each
plate. From this data it can be possible to calculate the percent inhibition
of COX-
2 and the ICSO values for the test compounds. Repeated investigations of COX-1
and COX-2 inhibition can be conducted over the course of several months. The
results are averaged and a single COX-1:COX-2 ratio is calculated.
Whole blood assays for COX-1 and COX-2 are known in the art such as
the methods described in C. Brideau, et al., A Human Whole Blood Assay for
Clinical Evaluation of Biochemical E~cacy of Cyclooxygenase Inhibitors,
Inflammation Research, Vol. 45, pp. 68-74 (1996). These methods may be
applied with feline, canine or human blood as needed.
' BIOLOGICAL METHOD 6
Carry ~eenan induced foot edema in rats
Male Sprague-Dawley rats (5 weeks old, Charles River Japan) can be
fasted overnight. A line can be drawn using a marker above the ankle on the
right
hind paw and the paw volume (VO) can be measured by water displacement using
a plethysmometer (Muromachi). Animals can be given orally either vehicle (0.1
%
methyl cellulose or 5% Tween 80) or a test compound (2.5 ml per 100g body
weight). One hour later, the animals can then be injected intradermally with 0
carrageenan (0.1 ml of 1 % w/v suspension in saline, Zushikagaku) into right
hind
paw (Winter et al., Proc. Soc. Exp. Biol. Med., 111, 544, 1962; Lombardino et
al.,
Arzneim. Forsch., 25, 1629, 1975) and three hours later, the paw volume (V3)
can
be measured and the increase in volume (V3-VO) calculated. Since maximum
inhibition attainable with classical NSAIDs is 60-70%, ED3o values can be
calculated.
BIOLOGICAL METHOD 7
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Gastric ulceration in rats:
The gastric ulcerogenicity of test compound can be assessed by a
modification of the conventional method (Ezer et al., J. Pharm. Pharmacol.,
28,
655, 1976; Cashin et al., J. Pharm. Pharmacol., 29, 330 - 336, 1977). Male
Sprague-Dawley rats (5 weeks old, Charles River Japan), fasted overnight, can
be
given orally either vehicle (0.1 % methyl cellulose or 5% Tween 80) or a test
compound (1 ml per 100g body weight). Six hours after, the animals can be
sacrificed by cervical dislocation. The stomachs can be removed and inflated
with
1 % formalin solution (l0 ml). Stomachs can be opened by cutting along the
greater curvature. From the number of rats that showed at least one gastric
ulcer
or haemorrhaging erosion (including ecchymosis), the incidence of ulceration
can
be calculated. Animals did not have access to either food or water during the
experiment.
BIOLOGICAL METHOD 8
Canine whole blood ex vivo determinations of COX-1 and COX-2 activity
inhibition
The in vivo inhibitory potency of a test compound against COX-1 and COX-2
activity may be evaluated using an ex vivo procedure on canine whole blood.
Three dogs can be dosed with 5 mg/kg of the test compound administered by oral
gavage in 0.5% methylcellulose vehicle and three dogs can be untreated. A zero-
hour blood sample can be collected from all dogs in the study prior to dosing,
followed by 2- and 8-hour post-dose blood sample collections. Test tubes can
be
prepared containing 2p,L of either (A) calcium ionophore A23187 giving a 50
~t.M
final concentration, which stimulates the production of thromboxane Bz (TXBZ)
for COX-1 activity determination; or of (B) lipopolysaccharide (LPS) to give a
10
p.g/mL final concentration, which stimulates the production of prostaglandin
E2
(PGE2) for COX-2 activity determination. Test tubes with unstimulated vehicle
can be used as controls. A 500 p,L sample of blood can be added to each of the
above-described test tubes, after which they can be incubated at 37°C
for one hour
in the case of the calcium ionophore-containing test tubes and overnight in
the
case of the LPS-containing test tubes. After incubation, 10 p.L of EDTA can be
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added to give a final concentration of 0.3%, in order to prevent coagulation
of the
plasma which sometimes occurs after thawing frozen plasma samples. The
incubated samples can be centrifuged at 4°C and the resulting plasma
sample of
200 p.L can be collected and stored at -20°C in polypropylene 96-well
plates. In
order to determine endpoints for this study, enzyme immunoassay (EIA) kits
available from Cayman can be used to measure production of TXBZ and PGE2,
utilizing the principle of competitive binding of tracer to antibody and
endpoint
determination by colorimetry. Plasma samples can be diluted to approximate the
range of standard amounts which would be supplied in a diagnostic or research
tools kit, i.e., l /S00 for TXB2 and 1/750 for PGEZ .
COX inhibition is observed when the measured percent inhibition is
greater than that measured for untreated controls. The percent inhibition in
the
above table is calculated in a straightforward manner in accordance with the
following equation:
' (PGEZ at t = 0) - (PGE2 at t = 2)
% Inhibition (2-hour) _
(PGEZ at t = 0)
Data Analysis:
Statistical program packages, SYSTAT (SYSTAT, INC.) and StatView
(Abacus Cencepts, Inc.) for Macintosh can be used. Differences between test
compound treated group and control group can be tested for using ANOVA. The
ICSO (ED30) values can be calculated from the equation for the log-linear
regression line of concentration (dose) versus percent inhibition.
The selective COX-2 inhibitors described above have been, or could have
been, identified by at least one of the methods described above and show, or
would show, ICso values of 0.001 p.M to 3 pM with respect to inhibition of COX-
2
in either the canine or human assays.
As mentioned above, COX-2 selectivity can be determined by ratio in
terms of ICSO value of COX-1 inhibition to COX-2 inhibition. In general, it
can be
said that a compound showing a COX-1/COX-2 inhibition ratio of more than 5
has sufficient COX-2 selectivity.
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The newly discovered ability of an allosteric carboxylic inhibitor of MMP-
13, or a pharmaceutically acceptable salt thereof, to inhibit cartilage
damage,
alleviate pain, and treat osteoarthritis may be established in animal models
as
described below. The activity of an invention combination for treating
cartilage
damage and pain and/or inflammation may be determined by the procedures of
Biological Methods 9 or 10 as described below.
BIOLOGICAL METHOD 9
Monosodium Iodoacetate-induced Osteoarthritis in Rat Model of Cartilage
Damage ("MIA Rat"):
One end result of the induction of osteoarthritis in this model, as
determined by histologic analysis, is the development of an osteoarthritic
condition within the affected joint, as characterized by the loss of Toluidine
blue
staining and formation of osteophytes. Associated with the histologic changes
is a
concentration-dependent degradation of joint cartilage, as evidenced by
affects on
hind-paw weight distribution of the limb containing the affected joint, the
presence of increased amounts of proteoglycan or hydroxyproline in the joint
upon biochemical analysis, or histopathological analysis of the osteoarthritic
lesions.
Generally, In the MIA Rat model on Day 0, the hind-paw weight
differential between the right arthritic joint and the left healthy joint of
male
Wistar rats (150 g) are determined with an incapacitance tester, model 2KG
(Linton Instrumentation, Norfolk, United Kingdom). The incapacitance tester
has
a chamber on top with an outwardly sloping front wall that supports a rat's
front
limbs, and two weight sensing pads, one for each hind paw, that facilitates
this
determination. Then the rats are anesthetized with isofluorine, and the right,
hind
leg knee joint is injected with I.0 mg of mono-iodoacetate ("MIA") through the
infrapatellar ligament. Injection of MIA into the joint results in the
inhibition of
glycolysis and eventual death of surrounding chondrocytes. The rats are
further
administered either an invention combination such as a combination, comprising
an allosteric carboxylic inhibitor of MMP-l3, or a pharmaceutically acceptable
salt thereof, with celecoxib, or a pharmaceutically acceptable salt thereof,
or
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valdecoxib, or a pharmaceutically acceptable salt thereof, or vehicle (in the
instant
case, water) daily for 14 days or 28 days. Both the allosteric carboxylic
inhibitor
of MMP-13, or a pharmaceutically acceptable salt thereof, and celecoxib, or a
pharmaceutically acceptable salt thereof, or valdecoxib, or a pharmaceutically
acceptable salt thereof, are, each independently, typically administered at a
dose
of 30 mg per kilogram of rat per day (30 mg/kg/day), but each component of the
combination may independently be administered at other doses such as, for
example, 10 mg/kg/day, 60 mg/kg/day, 90-mg/kg/day, or 100 mg/kg/day
according to the requirements of the combination being studied. It is well
within
the level of ordinary skill in the pharmaceutical arts to determine a proper
dosage
of an allosteric carboxylic inhibitor of MMP-13, or a pharmaceutically
acceptable
salt thereof, and celecoxib, or a pharmaceutically acceptable salt thereof, or
valdecoxib, or a pharmaceutically acceptable salt thereof, in this model.
Administration of the allosteric carboxylic inhibitor of MMP-13, or a
pharmaceutically acceptable salt thereof, and celecoxib, or a pharmaceutically
acceptable salt thereof, or valdecoxib, or a pharmaceutically acceptable salt
thereof, in this model is optionally by oral administration or intravenous
administration via an osmotic pump. Further, administration of the allosteric
carboxylic inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof,
and celecoxib, or a pharmaceutically acceptable salt thereof, or valdecoxib,
or a
pharmaceutically acceptable salt thereof, may be simultaneous as a co-
formulation
of both drugs, simultaneous by way of independent formulations of each drug of
the invention combination alone according to optimal drug delivery profiles,
or
non-simultaneous such as, sequential administration of an independent
formulation of one drug followed by, after some pre-determined period of time,
administration of an independent formulation of the other drug of the
invention
combination. After 7 and 14 days for a two-week study, or 7, 14, and 28 days
for a
four-week study, the hind-paw weight distribution is again determined.
Typically,
the animals administered vehicle alone place greater weight on their
unaffected
left hind paw than on their right hind paw, while animals administered an
invention combination show a more normal (i.e., more like a healthy animal)
weight distribution between their hind paws. This change in weight
distribution
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was proportional to the degree of joint cartilage damage. Percent inhibition
of a
change in hind paw joint function is calculated as the percent change in hind-
paw
weight distribution for treated animals versus control animals. For example,
for a
two week study,
Percent inhibition of a change in hind paw joint function
- l- (~W~) X 100
(OWc)
wherein: OWc is the hind-paw weight differential between the healthy left
limb and the arthritic limb of the control animal administered vehicle alone,
as
measured on Day 14; and
OWE is the hind-paw weight differential between the healthy left limb and
the arthritic limb of the animal administered an invention combination, as
measured on Day 14.
In order to measure biochemical or histopathological end points in the
MIA Rat model, some of the animals in the above study may be sacrificed, and
the amounts of free proteoglycan in both the osteoarthritic right knee joint
and the
contralateral left knee joint may be determined by biochemical analysis. The
amount of free proteoglycan in the contralateral left knee joint provides a
baseline
value for the amount of free proteoglycan in a healthy joint. The amount of
proteoglycan in the osteoarthritic right knee joint in animals administered an
invention combination, and the amount of proteoglycan in the osteoarthritic
right
knee joint in animals administered vehicle alone, are independently compared
to
the amount of proteoglycan in the contralateral left knee joint. The amounts
of
proteoglycan lost in the osteoarthritic right knee joints are expressed as
percent
loss of proteoglycan compared to the contralateral left knee joint control.
The
percent inhibition of proteoglycan loss, may be calculated as { [(proteoglycan
loss
from joint (%) with vehicle) - (proteoglycan loss from joint with an invention
combination)] = (proteoglycan loss from joint (%) with vehicle)} x 100.
The MIA Rat data that are expected from the analysis of proteoglycan loss
would establish that an invention combination is effective for inhibiting
cartilage
damage and inflammation and/or alleviating pain in mammalian patients,
including human.
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The results of these studies with oral dosing may be presented in tabular
format in the columns labelled "IJFL (%+/- SEM)", wherein IJFL means
Inhibition of Joint Function Limitation, "SDCES", wherein SDCES means
Significant Decrease In Cartilage Erosion Severity, and "SIJWHLE", wherein
SIJWHLE means Significant Increase in Joints Without Hind Limb Erosion.
The proportion of subjects without hind limb erosions may be analyzed via
an Exact Sequential Cochran-Annitage Trend test (SAS° Institute, 1999).
The
Cochran-Armitage Trend test is employed when one wishes to determine whether
the proportion of positive or "Yes" responders increases or decreases with
increasing levels of treatment. For the particular study, it is expected that
the
number of animals without joint erosions increased with increasing dose.
The ridit analysis may be used to determine differences in overall erosion
severity. This parameter takes into account both the erosion grade (0 = no
erosion, I = erosion extending into the superficial or middle layers, or II =
deep
layer erosion), and area (small, medium and large, quantified by dividing the
area
of the largest erosion in each score into thirds) simultaneously. The analysis
recognizes that each unit of severity is different, but does not assume a
mathematical relationship between units.
Another animal model for measuring effects of an invention combination
on cartilage damage and inflammation and/or pain is described below in
Biological Method 10.
BIOLOGICAL METHOD 10
Induction of Experimental Osteoarthritis in Rabbit ("EOA in Rabbit"):
Normal rabbits are anaesthetized and anteromedial incisions of the right
knees performed. The anterior cruciate ligaments are visualized and sectioned.
,The wounds are closed and the animals are housed in individual cages,
exercised,
and fed ad libitum. Rabbits are given either vehicle (water) or an invention
combination dosed three times per day with 30-mg/kg/dose or 10-mg/kg/dose.
each independently determined for the allosteric carboxylic inhibitor of MMP-
13,
or a pharmaceutically acceptable salt thereof, and celecoxib, or a
pharmaceutically
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acceptable salt thereof, or valdecoxib, or a pharmaceutically acceptable salt
thereof, but each drug of the combination may independently be administered at
other doses such as, for example, 3 times 20 mg/kg/day or 3 times 60 mg/kg/day
according to the requirements of the combination being studied. The rabbits
are
euthanized 8 weeks after surgery and the proximal end of the tibia and the
distal
end of the femur are removed from each animal.
Macroscopic Grading
The cartilage changes on the femoral condyles and tibial plateaus are
graded separately under a dissecting microscope (Stereozoom, Bausch & Lomb,
Rochester, NY). The depth of erosion is graded on a scale of 0 to 4 as
follows:
grade 0 = normal surface; Grade 1 = minimal fibrillation or a slight yellowish
discoloration of the surface; Grade 2 = erosion extending into superficial or
middle layers only; Grade 3 = erosion extending into deep layers; Grade
4 = erosion extending to subchondral bone. The surface area changes are
measured and expressed in mm2. Representative specimens may also be used for
histologic grading (see below).
Histologic Grading
Histologic evaluation is performed on sagittal sections of cartilage from
the lesional areas of the femoral condyle and tibial plateau. Serial sections
(5 um)
are prepared and stained with safranin-O. The severity of OA lesions is graded
on
a scale of 0 - 14 by two independent observers using the histologic-
histochemical
scale of Mankin et al. This scale evaluates the severity of OA lesions based
on the
loss of safranin-O staining (scale 0 - 4), cellular changes (scale 0 - 3),
invasion of
tidemark by blood vessels (scale 0 - 1 ) and structural changes (scale 0 - 6).
On this
latter scale, 0 indicates normal cartilage structure and 6 indicates erosion
of the
cartilage down to the subchondral bone. The scoring system is based on the
most
severe histologic changes in the multiple sections.
Representative specimens of synovial membrane from the medial and
lateral knee compartments are dissected from underlying tissues. The specimens
are fixed, embedded, and sectioned (5 um) as above, and stained with
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hematoxylin-eosin. For each compartment, two synovial membrane specimens are
examined for scoring purposes and the highest score from each compartment is
retained. The average score is calculated and considered as a unit for the
whole
knee. The severity of synovitis is graded on a scale of 0 to 10 by two
independent
observers, adding the scores of 3 histologic criteria: synovial lining cell
hyperplasia (scale 0 - 2); vinous hyperplasia (scale 0 - 3); and degree of
cellular
infiltration by mononuclear and polymorphonuclear cells (scale 0 - 5): 0
indicates
normal structure.
Statistical Analysis
Mean values and SEM is calculated and statistical analysis was done using
the Mann-Whitney U-test.
The results of these studies would be expected to show that an invention
combination would reduce the size of the lesion on the tibial plateaus, and
perhaps
the, damage in the tibia or on the femoral condyles, as well as show pain
alleviating effects if measured. In conclusion, these results would show that
an
invention combination would have significant inhibition effects on the damage
to
cartilage and pain.
The foregoing studies would establish that an invention combination is
effective for the inhibition of cartilage damage and inflammation and/or
alleviating pain, and thus useful for the treatment of osteoarthritis or
rheumatoid
arthritis in human, and other mammalian disorders. Such a treatment offers a
distinct advantage over existing treatments that only modify pain or
inflammation
or and other secondary symptoms. The effectiveness of an invention combination
in this model would indicate that the invention combination will have
clinically
useful effects in preventing and/or treating cartilage damage, pain and/or
inflammation.
Administration according to the invention method of celecoxib, or a
pharmaceutically acceptable salt thereof, or valdecoxib, or a pharmaceutically
acceptable salt thereof, and an allosteric carboxylic inhibitor of MMP-13, or
a
pharmaceutically acceptable salt thereof, to a mammal to treat the diseases
listed
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above is preferably, although not necessarily, accomplished by administering
the
compound, or a salt thereof, in a pharmaceutical dosage form.
Celecoxib, or a pharmaceutically acceptable salt thereof, or valdecoxib, or
a pharmaceutically acceptable salt thereof, and allosteric carboxylic
inhibitors of
MMP-13, or a pharmaceutically acceptable salt thereof, can be prepared and
administered according to the invention method in a wide variety of oral and
parenteral pharmaceutical dosage forms. Thus, celecoxib, or a pharmaceutically
acceptable salt thereof, or valdecoxib, or a pharmaceutically acceptable salt
thereof, and the allosteric carboxylic inhibitors of MMP-13, or a
pharmaceutically
~ acceptable salt thereof, can be administered by injection, that is,
intravenously,
intramuscularly, intracutaneously, subcutaneously, intraduodenally, or
intraperitoneally. Also, celecoxib, or a pharmaceutically acceptable salt
thereof, or
valdecoxib, or a pharmaceutically acceptable salt thereof, and the allosteric
carboxylic inhibitors of MMP-13, or a pharmaceutically acceptable salt
thereof,
can be administered by inhalation, for example, intranasally. Additionally,
celecoxib, or a pharmaceutically acceptable salt thereof, or valdecoxib, or a
pharmaceutically acceptable salt thereof, and the allosteric carboxylic
inhibitors of
MMP-13, or a pharmaceutically acceptable salt thereof, can be administered
transdermally. It will be obvious to those skilled in the art that the
following
dosage forms may comprise as the active components celecoxib, or a
pharmaceutically acceptable salt thereof, or valdecoxib, or a pharmaceutically
acceptable salt thereof, and an allosteric carboxylic inhibitor of MMP-13, or
a
pharmaceutically acceptable salt thereof. The active compounds generally are
present in a concentration of about 5% to about 95% by weight of the
formulation.
For preparing pharmaceutical compositions from celecoxib, or a
pharmaceutically acceptable salt thereof, or valdecoxib, or a pharmaceutically
acceptable salt thereof, and the allosteric carboxylic inhibitors of MMP-13,
or a
pharmaceutically acceptable salt thereof, (i.e., the active components)
pharmaceutically acceptable carriers can be either solid or liquid. Solid form
preparations are preferred. Solid form preparations include powders, tablets,
pills,
capsules, cachets, suppositories, and dispersible granules. A solid carrier
can be
one or more substances which may also act as diluents, flavoring agents,
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solubilizers, lubricants, suspending agents, binders, preservatives, tablet
disintegrating agents, or an encapsulating material.
In powders, the carrier is a finely divided solid which is in a mixture with
the finely divided active component. Powders suitable for intravenous
administration or administration by injection may be lyophilized.
In tablets, the active component is mixed with the carrier having the
necessary binding properties in suitable proportions and compacted in the
shape
and size desired.
The powders and tablets preferably contain from about 5% to about 70%,
total, of the active component. Suitable carriers are magnesium carbonate,
magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin,
tragacanth,
methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa
butter, and the like. The term "preparation" is intended to include the
formulation
of the active component with encapsulating material as a carrier providing a
capsule in which the active component, with or without other carriers, is
surrounded by a carrier, which is thus in association with it. Similarly,
cachets and
lozenges are included. Tablets, powders, capsules, pills, cachets, and
lozenges can
be used as solid dosage forms suitable for oral administration.
For preparing suppositories, a low melting wax, such as a mixture of fatty
acid glycerides or cocoa butter, is first melted and the active component is
dispersed homogeneously therein, as by stirring. The molten homogenous mixture
is then poured into convenient sized molds, allowed to cool, and thereby to
solidify.
Liquid form preparations include solutions, suspensions, and emulsions,
for example, water or water propylene glycol solutions. For parenteral
injection,
liquid preparations can be formulated in solution in aqueous polyethylene
glycol
solution.
Aqueous solutions suitable for oral use can be prepared by dissolving the
active component in water and adding suitable colorants, flavors, stabilizing,
and
thickening agents as desired.
Aqueous suspensions suitable for oral use can be made by dispersing the
finely divided active component in water with viscous material, such as
natural or
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synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and
other well-known suspending agents.
Also included are solid form preparations which are intended to be
converted, shortly before use, to liquid form preparations for oral
administration.
Such liquid forms include solutions, suspensions, and emulsions. These
preparations may contain, in addition to the active component, colorants,
flavors,
stabilizers, buffers, artificial and natural sweeteners, dispersants,
thickeners,
solubilizing agents, and the like.
The pharmaceutical preparation is preferably in unit dosage form. In such
form, the preparation is subdivided into unit doses containing an appropriate
quantity of the active component. The unit dosage form can be a packaged
preparation, the package containing discrete quantities of preparation, such
as
packeted tablets, capsules, and powders in vials or ampoules. Also, the unit
dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be
the
appropriate number of any of these in packaged form.
The quantity of active component in a unit dose preparation may be varied
or adjusted from 0.01 to 1000 mg, preferably 1 to 500 mg according to the
particular application and the potency of the active components. The
composition
can, if desired, also contain other compatible therapeutic agents.
In therapeutic use as agents to treat the above-listed diseases, the
allosteric
carboxylic inhibitors of MMP-13, or a pharmaceutically acceptable salt
thereof, or
a combination of the same with valdecoxib, or a pharmaceutically acceptable
salt
thereof, or celecoxib, or a pharmaceutically acceptable salt thereof, are
administered at a dose that is effective for treating at least one symptom of
the
disease or disorder being treated. The initial dosage of about 1 mg/kg to
about
100 mg/kg daily of the active component will be effective. A daily dose range
of
about 25 mg/kg to about 75 mg/kg of the active component is preferred. The
dosages, however, may be varied depending upon the requirements of the
patient,
the severity of the condition being treated, and the particular allosteric
carboxylic
inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof, and
valdecoxib, or a pharmaceutically acceptable salt thereof, or celecoxib, or a
pharmaceutically acceptable salt thereof, being employed in the invention
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combination. Determination of the proper dosage for a particular situation is
within the skill of the art as described above. Typical dosages will be from
about
0.1 mg/kg to about 500 mg/kg, and ideally about 25 mg/kg to about 250 mg/kg,
such that it will be an amount that is effective to treat the particular
disease or
disorder being treated.
A preferred composition for dogs comprises an ingestible liquid peroral
dosage form selected from the group consisting of a solution, suspension,
emulsion, inverse emulsion, elixir, extract, tincture and concentrate,
optionally to
be added to the drinking water of the dog being treated. Any of these liquid
dosage forms, when formulated in accordance with methods well known in the
art,
can either be administered directly to the dog being treated, or may be added
to
the drinking water of the dog being treated. The concentrate liquid form, on
the
other hand, is formulated to be added first to a given amount of water, from
which
an aliquot amount may be withdrawn' for administration directly to the dog or
addition to the drinking water of the dog.
A preferred composition provides delayed-, sustained- and/or controlled-
release of valdecoxib, or a pharmaceutically acceptable salt thereof, or
celecoxib,
or a pharmaceutically acceptable salt thereof, and the allosteric carboxylic
inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof. Such
preferred compositions include all such dosage forms which produce >_ 40%
inhibition of cartilage degradation, and result in a plasma concentration of
the
active component of at least 3 fold the active component's ED4o for at least 2
hours; preferably for at least 4 hours; preferably for at least 8 hours; more
preferably for at least 12 hours; more preferably still for at least 16 hours;
even
more preferably still for at least 20 hours; and most preferably for at least
24
hours. Preferably, there is included within the above-described dosage forms
those which produce >_ 40% inhibition of cartilage degradation, and result in
a
plasma concentration of the active component of at least 5 fold the active
component's ED4o for at least 2 hours, preferably for at least 2 hours,
preferably
for at least 8 hours, more preferably for at least 12 hours, still more
preferably for
at least 20 hours and most preferably for at least 24 hours. More preferably,
there
is included the above-described dosage forms which produce >_ 50% inhibition
of
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cartilage degradation, and result in a plasma concentration of the active
component of at least 5 fold the active component's ED4o for at least 2 hours,
preferably for at least 4 hours, preferably for at least 8 hours, more
preferably for
at least 12 hours, still more preferably for at least 20 hours and most
preferably for
at least 24 hours.
The following Formulation Examples 1 to 8 illustrate the invention
pharmaceutical compositions wherein the allosteric carboxylic inhibitor of MMP-
13, or a pharmaceutically acceptable salt thereof, and valdecoxib, or a
pharmaceutically acceptable salt thereof, or celecoxib, or a pharmaceutically
acceptable salt thereof, are formulated separately, each independently as
described, When the formulations comprise the allosteric carboxylic inhibitor
of
MMP-13, or a pharmaceutically acceptable salt thereof, and a pharmaceutically
acceptable carrier, diluent, or excipient, they contain a cartilage damage
treating
effective amount or an anti-osteoarthritic effective amount of the allosteric
carboxylic inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof.
When the formulations comprise valdecoxib, or a pharmaceutically acceptable
salt
thereof, or celecoxib, or a pharmaceutically acceptable salt thereof, they
contain a
pain alleviating effective amount or an anti-inflammatory effective amount of
valdecoxib or celecoxib. The examples are representative only, and are not to
be
construed as limiting the invention in any respect.
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FORMULATION EXAMPLE 1
Tablet Formulation:
Ingredient Amount (mg)
An allosteric carboxylic inhibitor 25
of MMP-13, or
celecoxib, or valdecoxib
Lactose 50
Cornstarch (for mix) 10
Cornstarch (paste) 10
Magnesium stearate (1%) 5
Total 100
The allosteric carboxylic inhibitor of MMP-13, or celecoxib, or
valdecoxib, lactose, and cornstarch (for mix) are blended to uniformity. The
cornstarch (for paste) is suspended in 200 mL of water and heated with
stirring to
form a paste. The paste is used to granulate the mixed powders. The wet
granules
are passed through a No. 8 hand screen and dried at 80°C. The dry
granules are
lubricated with the 1 % magnesium stearate and pressed into a tablet. Such
tablets
can be administered to a human from one to four times a day for inhibiting
cartilage damage or treating osteoarthritis.
FORMULATION EXAMPLE 2
Coated Tablets:
The tablets of Formulation Example 1 are coated in a customary manner
with a coating of sucrose, potato starch, talc, tragacanth, and colorant.
FORMULATION EXAMPLE 3
Injection vials:
The pH of a solution of 500 g of an allosteric carboxylic inhibitor of
MMP-13, or celecoxib, or valdecoxib and 5 g of disodium hydrogen phosphate is
adjusted to pH 6.5 in 3 L of double-distilled water using 2 M hydrochloric
acid.
The solution is sterile altered, and the filtrate is filled into injection
vials,
lyophilized under sterile conditions, and aseptically sealed. Each injection
vial
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contains 25 mg of the allosteric carboxylic inhibitor of MMP-13, or celecoxib,
or
valdecoxib.
FORMULATION EXAMPLE 4
Suppositories:
A mixture of 25 g of an allosteric carboxylic inhibitor of MMP-13, or
celecoxib, or valdecoxib, 100 g of soya lecithin, and 1400 g of cocoa butter
is
fused, poured into molds, and allowed to cool. Each suppository contains 25 mg
of the allosteric carboxylic inhibitor of MMP-13, or celecoxib, or valdecoxib.
FORMULATION EXAMPLE 5
Solution:
A solution is prepared from 1 g of an allosteric carboxylic inhibitor of
MMP-13, or celecoxib, or valdecoxib, 9.38 g of NaH2P04~12H20, 28.48 g of
Na2HP04~ 12H20, and 0.1 g benzalkonium chloride in 940 mL of double-distilled
water. The pH of the solution is adjusted to pH 6.8 using 2 M hydrochloric
acid.
The solution is diluted to 1.0 L with double-distilled water, and sterilized
by
irradiation. A 25 mL volume of the solution contains 25 mg of the allosteric
carboxylic inhibitor of MMP-13, or celecoxib, or valdecoxib.
FORMULATION EXAMPLE 6
Ointment:
500 mg of an allosteric carboxylic inhibitor of MMP-13, or celecoxib, or
valdecoxib is mixed with 99.5 g of petroleum jelly under aseptic conditions. A
5 g
portion of the ointment contains 25 mg of the allosteric carboxylic inhibitor
of
MMP-13, or celecoxib, or valdecoxib.
FORMULATION EXAMPLE 7
Capsules:
2 kg of an allosteric carboxylic inhibitor of MMP-13, or celecoxib, or
valdecoxib are filled into hard gelatin capsules in a customary manner such
that
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each capsule contains 25 mg of the allosteric carboxylic inhibitor of MMP-13,
or
celecoxib, or valdecoxib.
FORMULATION EXAMPLE 8
Amaoules:
A solution of 2.5 kg of an allosteric carboxylic inhibitor of MMP-13, or
celecoxib, or valdecoxib is dissolved in 60 L of double-distilled water. The
solution is sterile filtered, and the filtrate is filled into ampoules. The
ampoules are
lyophilized under sterile conditions and aseptically sealed. Each ampoule
contains
25 mg of the allosteric carboxylic inhibitor of MMP-13, or celecoxib, or
valdecoxib.
The following Formulation Examples 9 to 16 illustrate the invention
pharmaceutical compositions containing an invention combination iri a single
formulation with a pharmaceutically acceptable carrier, diluent, or excipient.
The
examples are representative only, and are not to be construed as limiting the
invention in any respect.
FORMULATION EXAMPLE 9
Tablet Formulation:
Ingredient Amount (mg)
An allosteric carboxylic inhibitor25
of MMP-13
Valdecoxib or celecoxib 20
Lactose 50
Cornstarch (for mix) 10
Cornstarch (paste) 10
Magnesium stearate (1%) 5
Total 120
The allosteric carboxylic inhibitor of MMP-13, valdecoxib or celecoxib,
lactose, and cornstarch (for mix) are blended to uniformity. The cornstarch
(for
paste) is suspended in 200 mL of water and heated with stirring to form a
paste.
The paste is used to granulate the mixed powders. The wet granules are passed
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through a No. 8 hand screen and dried at 80°C. The dry granules are
lubricated
with the 1 % magnesium stearate and pressed into a tablet. Such tablets can be
administered to a human from one to four times a day for treatment of one of
the
above-listed diseases.
FORMULATION EXAMPLE l 0
Coated Tablets:
The tablets of Formulation Example 9 are coated in a customary manner
with a coating of sucrose, potato starch, talc, tragacanth, and colorant.
FORMULATION EXAMPLE 11
Iniecti' on vials:
The pH of a solution of 250 g of valdecoxib or celecoxib, 500 g of an
allosteric carboxylic inhibitor of MMP-13, and 5 g of disodium hydrogen
phosphate is adjusted to pH 6.5 in 3 L of double-distilled water using 2 M
hydrochloric acid. The solution is sterile filtered, and the filtrate is
filled into
injection vials, lyophilized under sterile conditions, and aseptically sealed.
Each
injection vial contains 12.5 mg of valdecoxib or celecoxib and 25 mg of the
allosteric carboxylic inhibitor of MMP-l3.
FORMULATION EXAMPLE 12
Suppositories:
A mixture of 50 g of valdecoxib or celecoxib, 25 g of an allosteric
carboxylic inhibitor of MMP-13, 100 g of soya lecithin, and 1400 g of cocoa
butter is fused, poured into molds, and allowed to cool. Each suppository
contains
50 mg of valdecoxib or celecoxib and 25 mg of the allosteric carboxylic
inhibitor
of MMP-13.
FORMULATION EXAMPLE 13
Solution:
A solution is prepared from 0.5 g of valdecoxib or celecoxib, 1 g of an
allosteric carboxylic inhibitor of MMP-l 3, 9.38 g of NaH2P04~ 12H20, 28.48 g
of
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Na2HP04~12H20, and 0.1 g benzalkonium chloride in 940 mL of double-distilled
water. The pH of the solution is adjusted to pH 6.8 using 2 M hydrochloric
acid.
The solution is diluted to 1.0 L with double-distilled water, and sterilized
by
irradiation. A 25 mL volume of the solution contains 12.5 mg of valdecoxib or
celecoxib and 25 mg of the allosteric carboxylic inhibitor of MMP-13.
FORMULATION EXAMPLE 14
Ointment:
100 mg of valdecoxib or celecoxib, 500 mg of an allosteric carboxylic
inhibitor of MMP-13 is mixed with 99.4 g of petroleum jelly under aseptic
conditions. A 5 g portion of the ointment contains 5 mg of valdecoxib or
celecoxib and 25 mg of the allosteric carboxylic inhibitor of MMP-13.
FORMULATION EXAMPLE 15
Capsules:
2 kg of valdecoxib or celecoxib and 20 kg of an allosteric carboxylic
inhibitor of MMP-13 are filled into hard gelatin capsules in a customary
manner
such that each capsule contains 25 mg of valdecoxib or celecoxib and 250 mg of
the allosteric carboxylic inhibitor of MMP-13.
FORMULATION EXAMPLE 16
Ampoules:
A solution of 2.5 kg of valdecoxib or celecoxib and 2.5 kg of an allosteric
carboxylic inhibitor of MMP-13 is dissolved in 60 L of double-distilled water.
The solution is sterile filtered, and the filtrate is filled into ampoules.
The
ampoules are lyophilized under sterile conditions and aseptically sealed. Each
ampoule contains 25 mg each of valdecoxib or celecoxib and the allosteric
carboxylic inhibitor of MMP-13.
While it may be desirable to formulate valdecoxib or celecoxib and an
allosteric carboxylic inhibitor of MMP-13, or a pharmaceutically acceptable
salt
thereof, together in one capsule, tablet, ampoule, solution, and the like, for
simultaneous administration, it is not necessary for the purposes of
practicing the
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invention methods. Valdecoxib or celecoxib and an allosteric carboxylic
inhibitor
of MMP-13, or a pharmaceutically acceptable salt thereof, of an invention
combination alternatively can each be formulated independently in any form
such
as, for example, those of any one Formulation Examples 1 to l 6, and
administered
tb a patient either simultaneously or at different times.
The following examples illustrate the invention pharmaceutical
compositions containing discrete formulations of the active components of the
invention combination and a pharmaceutically acceptable carrier, diluent, or
excipient. The examples are representative only, and are not to be construed
as
limiting the invention in any respect.
FORMULATION EXAMPLE 17
Tablet Formulation of an allosteric carboxylic inhibitor of MMP-13:
Ingredient Amount (mg)
An allosteric carboxylic inhibitor of MMP-13 25
Lactose 50
Cornstarch (for mix) 10
Cornstarch (paste) 10
Magnesium stearate (1 %) 5
Total l 00
An allosteric carboxylic inhibitor of MMP-l3, lactose, and cornstarch (for
mix) are blended to uniformity. The cornstarch (for paste) is suspended in 200
mL
of water and heated with stirring to form a paste. The paste is used to
granulate the
mixed powders. The wet granules are passed through a .No. 8 hand screen and
dried at 80°C. The dry granules are lubricated with the 1 % magnesium
stearate
and pressed into a tablet.
Injection vial formulation of valdecoxib or celecoxib:
The pH of a solution of 500 g of valdecoxib or celecoxib and 5 g of
disodium hydrogen phosphate is adjusted to pH 6.5 in 3 L of double-distilled
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water using 2 M hydrochloric acid. The solution is sterile filtered, and the
filtrate
is filled into injection vials, lyophilized under sterile conditions, and
aseptically
sealed. Each injection vial contains 25 mg of valdecoxib or celecoxib.
Such tablets containing the allosteric carboxylic inhibitor of MMP-13 can
be administered to a human from one to four times a day for treatment of the
above-listed diseases, and the injection solutions containing valdecoxib or
celecoxib can be administered to a human I or 2 times per day, wherein the
administration by injection is optionally simultaneous with administration of
the
tablets or at different times, for the treatment of one of the above-listed
diseases.
l0 FORMULATION EXAMPLE 18
Coated Tablets containing an allosteric carboxylic inhibitor of MMP-13:
The tablets of Formulation Example 17 are coated in a customary manner
with a coating of sucrose, potato starch, talc, tragacanth, and colorant.
Capsules containing valdecoxib or celecoxib:
2 kg of valdecoxib or celecoxib are filled into hard gelatin capsules in a
customary manner such that each capsule contains 25 mg of valdecoxib or
celecoxib.
Such coated tablets containing the allosteric carboxylic inhibitor of MMP-
13 can be administered to a human from one to four times a day for treatment
of
the above-listed diseases, and the capsules containing valdecoxib or celecoxib
can
be administered to a human 1 or 2 times per day, wherein the administration of
the
capsules is optionally simultaneous with administration of the tablets or at
different times, for the treatment of one of the above-listed diseases.
Still further, it should be appreciated that the invention methods
comprising administering an invention combination to a mammal to treat
diseases
or disorders listed above may be used to treat different diseases
simultaneously.
For example, administration of valdecoxib or celecoxib in accordance with the
invention combination may be carried out as described above to treat
inflammation, arthritic pain, pain associated with menstrual cramping, and
migraines, while an allosteric carboxylic inhibitor of MMP-13, or a
CA 02495432 2005-O1-06
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pharmaceutically acceptable salt thereof, may be administered to treat OA or
inhibit cartilage damage.
As shown above, the invention method offers a distinct advantage over
existing treatments for diseases such as OA that comprise cartilage damage,
wherein the existing treatments modify pain or secondary symptoms, but do not
show a disease modifying effect.
While the invention has been described and illustrated with reference to
certain particular embodiments thereof, those skilled in the art will
appreciate that
various adaptations, changes, modifications, substitutions, deletions, or
additions
of procedures and protocols may be made without departing from the spirit and
scope of the invention. It is intended, therefore, that the invention be
defined by
the scope of the claims that follow and that such claims be interpreted as
broadly
as is reasonable.
Having described the invention method, various embodiments of the
invention are hereupon claimed.
